EMA Module 16 Draft Risk Minimisation Measures

Jun 19, 2013

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

In early June the EMA released a draft version of its Good PV Practices Module XVI on Risk Minimisation Measures: Selection of tools and effectiveness indicators.  See https://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/06/WC500144010.pdf

This document discusses in detail risk minisation measures included in Risk Management Plans (RMPs).  It largely covers the same things that the US FDA has called “Elements to ensure safe use” (ETASUs).  As this is a draft, the EMA is calling for comments by August 5, 2013.  This module is to read and used in conjunction with Module 5 on risk Management Systems.

In a nutshell, there are no real surprises in this document and it is entirely consistent with earlier communications from the EMA and member states and also consistent with FDA’s ETASUs and approach to risk.  Here is a brief summary.  See the document for more detail particularly about generics and hybrids.

Risk Minimisation Plans (NOT abbreviated RMP which is used for Risk Management Plans) include measures which are “Public health interventions intended to prevent or reduce the occurrence of ARs associated with the exposure to a medicine, or to reduce their severity or impact on the patient should they occur.” They may be routine and used for all products approved in the EU or there may be additional measures for selected products.

The goal of all of the routine and special measures is to  optimize the safe and effective use of the product throughout its life-cycle.  This means reducing the AR burden, optimize the benefits, target the appropriate patient population for selection or exclusion for use of the product and to ensure the best possible treatment management (dosing regimen, lab tests etc.).  In other words, as they say, “The right drug, at the right dose, at the right time, to the right patient, by the right prescriber, and with the right information and monitoring.”

The MAH and Qualified Person for PV hold the ultimate responsibility for the RMP and minimization measures.  The usual quality measures should be in place including updating the measures if new information becomes available, version control and good documentation practices, tracking, analysis of results etc.  The EMA notes that the RMP and measures are subject to CA inspection.

Routine measures:  These are the standard procedures all MA holders do in pharmacovigilance.  This includes the labeling, the summary of product characteristics (SmPC), the package leaflet, the package size and design and the legal prescription status of the product.  All measures, whether routine or customized, should have a clear objective and defined measures of success with milestones.

Each measure should be linked to a specific safety concern in the RMP to include:

  • Rationale: Set out the rationale for the proposed additional measures including defined objectives for each of the measures proposed.
  • Description of the measures: Describe the measures, including a description of the tools that will be used.
  • Implementation plan: Provide a detailed proposal for the implementation of the measures (e.g. setting and timing or frequency of intervention, details of the target audience);
  • Evaluation plan: Provide a detailed plan with milestones for evaluating the effectiveness of the measures in terms of overall health outcome measures (e.g. reduction of risk).

Customized Risk Minimisation Measures:  These are customized in purpose, design, target audience etc. to ensure the appropriate patient selection and can include education programs, controlled access or other measures.

Educational Programs: These are actionable measures taken to minimize risk by teaching or training.  They can be in any format including paper, audio, video, web, in person etc.  The content should be aligned with the SmPC and package leaflet and must avoid promotional elements.

Such programs must be clearly defined in scope and should include unambiguous statements regarding the risks to be addressed with the tool, the specific steps to be taken by health care practitioners &/or patients to minimise the risks. They should contain:

  • A statement that the material is mandatory as a condition of marketing
  • Guidance on prescribing, including patient selection, testing and monitoring
  • Guidance on the management of the risks
  • Guidance on how and where to report ARs of interest.
  • Specifics on selection of patients, dosage, testing & monitoring, special administration or dispensing, details of information given to patients.
  • Various formats are feasible including a checklist, brochure, poster etc.

Tools for patients and caregivers (called “carers” by the EMA) should enhance their awareness of the signs and symptoms of specific ARs  causing the need for additional risk minimisation measures and on what to do if the symptoms occur. Formats are flexible and can include a diary, alert card or a portable and easily carried wallet card.

Controlled Access Programs: These are customized to the product or situation.  They may include:

  • Specific testing &/or examination of the patient (e.g. LFTs, pregnancy test, ECGs before & during treatment)
  • Prescriber, dispenser &/or patient documenting their receipt and understanding of information
  • Systematic patient follow-up through enrolment in a patient registry
  • Dispensing only in registered & approved pharmacies.

Pregnancy Prevention Programs (PPP): These are interventions aiming to minimise pregnancy when starting or during treatment with a medicinal product with known or potential teratogenic effects. They are aimed mainly at females but may also apply in males where use would have a negative effect on pregnancy outcome.  They can be:

  • Educational measures targeting HCPs and patients to inform them on the teratogenic risk and required actions (e.g. use more than one method of contraception etc.)
  • Controlled access to ensure that a pregnancy test is carried out and is negative as verified by the HCP before prescription or dispensing of the medicinal product
  • Prescription limited to a maximum of 30 days supply;
  • Counseling in the event of inadvertent pregnancy.
  • May be appropriate to continue for a period after end of treatment (e.g. 3 months).

Direct Health Care Professional Communication (DHPC): This is a communication by any means from the MA holder or the Competent Authority (CA) directly to the practitioner.

Implementation of risk minimization measures: The MAH and CA should carefully consider the timing and the procedures for the measures.  A one-off/one time distribution of tools before or at the time of product launch may not be sufficient.  It may be necessary to do periodic follow up reminders.  The EMA repeats that the educational material must be clearly distinct from and distributed separately from any promotional material the MAH produces.  The Member State CA should review the material and quality assurance measures should be in place to ensure and verify quality.

Effectiveness measurement of the risk minimization measures:  The must be an evaluation of the measures to determine whether they are working and if not, why not.  Measurements should not be qualitative but should include quantitative metrics.  These metrics should measure three things:

  • The process itself (is the implementation going as planned. For example, are the brochures being sent and received)
  • The impact on knowledge and behavior of the target audience (are HCPs and patients actually doing what they are instructed to do)
  • Outcomes (are they achieving what the objective called for)

A conclusion should be drawn by the MAH and CA on whether the measures are successful, whether changes are needed or whether the measure can be stopped.

Process Indicators/Metrics:

  • Use measures of distribution to focus on the appropriateness of the tool for the audience (e.g. adequate language, pictures, diagrams) & assess whether the materials were actually received by the target population
  • Assess clinical knowledge acquired from the tool using rigorous survey methods with standard questions done via phone, interview or self-administered.  Repeat over time.  Monitor attitude or representative populations with a randomized & adequate sample size.
  • Assess clinical actions such as prescribing behavior.  Can use prescription data linked to patient records or other means.  Look at co-prescribing, compliance with lab monitoring etc. Use rigorous statistical methods.

Outcome Indicators:

  • Safety outcomes should be measured in a rigorous way e.g. incidence rates of an AR in a post approval safety study).
  • Try to obtain frequency before and after the RMP is implemented. If not feasible, use a predefined reference from literature, historical data etc.
  • Spontaneous reporting frequency is NOT acceptable as a rule for outcome indicators.
  • RMPs should be similar for branded and generics/hybrids.

There is a fairly extensive section on the internal EMA/Member States regulatory network.  It can briefly be summarized as noting that for centrally approved products, the PRAC & CHMP requirements will be conditions for use of the product; that is, the MAH must do what is told to them by these bodies.  Individual EU MS’s may tailor RMPs and add additional measures nationally.  The EMA via the PRAC will monitor RMPs  The PRAC will evaluate the RMPs, protocols & outcomes.  The CAs of the MSs have national level responsibility for RMPs and they may add additional measures to RMPs for generics/hybrids. See the document for more details.

MAH Obligations: The MAH must define all RMP objectives  and, after approval at the EU level, implement at the national level working jointly with the Member States CAs.  The MAH must monitor outcomes and report them in RMP updates and PSURs.

Health Care Professionals & Patients’ Obligations on RMP Implementation: None.  But cooperation is encouraged.

PSURs/PBRERs and RMPs: An effectiveness evaluation must be done and must:

  • Describe the implemented risk minimisation measures, objective(s), and the selected process and outcome indicators.
  • Analyze the nature of the ARs including severity and preventability.
  • Examine the delivery of the risk minimisation measures in routine clinical practice, including any deviation from the original plan.
  • Include outcome indicators (i.e. AR frequency and/or severity) should normally be the key endpoint when assessing the attainment of risk minimisation measures objectives.
  • Proposals for change/update should be included.

Updates & Changes to the RMP: These should be done as appropriate with more frequent updates for products with more risk.

Finally, the EMA notes that they will make public a summary of the RMP and minimization measures and tools.  They will issue a public assessment report (EPAR), the product characteristics information, package leaflets, conditions of the MA, required registries and any deadlines or conditions imposed on the MAH.

There is a detailed set of appendices covering sampling procedures and recruitment strategy, the design and administration of the data collection instruments, analytical/statistical approaches and comments on ethics and privacy.  See the module for full details.

Bottom line:  No major surprises here at all.  This is consistent with US FDA approach though the RMP is entirely different in content and format from the US REMS.  However, the resulting ETASUs or minimization measures look remarkably similar.  It is hoped that the regulatory agencies in the US and EU as well as elsewhere will be consistent in the application of the tools and measures put in place in their countries.  However, of necessity, given the differences in the way medicine is practiced and they way products are sold and distributed this may not be as easily harmonized as we hope.  It is also hoped that the health authorities will look at these systems now in place in several years time and see if they really are improving health care.