European Medicines Agency
Post-authorisation Evaluation of Medicines for Human Use
7 Westferry Circus, Canary Wharf, London, E14 4HB, UK
London, 14 November 2005
Doc. Ref. EMEA/CHMP/96268/2005
COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE
(CHMP)
GUIDELINE ON RISK MANAGEMENT SYSTEMS FOR MEDICINAL
PRODUCTS FOR HUMAN USE
DRAFT AGREED BY PhVWP
26 July 2005 ADOPTION BY CHMP FOR RELEASE FOR CONSULTATION 27 July 2005 END OF CONSULTATION (DEADLINE FOR COMMENTS)    5 October 2005 ADOPTION BY CHMP
14 November 2005 DATE FOR COMING INTO EFFECT 20 November 2005
THIS GUIDELINE WILL BE INCLUDED AS CHAPTER I.3 OF VOLUME 9
GUIDELINE ON RISK MANAGEMENT SYSTEMS  FOR MEDICINAL PRODUCTS FOR HUMAN USE
1.INTRODUCTION (background) 4
2.SCOPE 5
3.LEGAL BASIS 5
characterise4.RISK MANAGEMENT DESCRIPTION AND THE REQUIREMENTS FOR
APPLICANTS AND MARKETING AUTHORISATION HOLDERS 6 4.1Description of the risk management system. 6 4.2EU Risk Management Plan (EU-RMP) 7 4.3Situations when an EU-RMP is
required 7
4.3.1Authorisations via the centralised procedure 8
4.3.2Authorisations via the mutual recognition or decentralised procedure. 8 4.4Location in the dossier 8 4.5Safety Specification 8
4.5.1Non-clinical 9
4.5.2Clinical 9
4.5.2.1Limitations of the human safety database 9
4.5.2.2Populations not studied in the pre-authorisation  phase 10
4.5.2.3Adverse Events/Adverse Reactions 10
4.5.2.4Identified and potential interactions including food-drug and drug-drug interactions
12
4.5.2.5Epidemiology 12
4.5.2.6Pharmacological class effects 12
4.5.2.7Additional EU requirements 12
4.5.3Summary 13 4.6Pharmacovigilance Plan 13
4.6.1Routine Pharmacovigilance 13
4.6.2Additional pharmacovigilance activities and action plans 13
4.6.3Action Plan for safety concerns 14 4.7Evaluation of the need for  risk minimisation activities 14
4.7.1Potential for medication errors 15 4.8The risk minimisation plan 15 4.9Risk minimisation activities 16
4.9.1Risk communication 16 4.10The Marketing Authorisation 16 4.11Ensuring the effectiveness of risk minimisation activities 17
4.11.1Assessment of risk minimisation 17 4.12Summary of activities in the EU-RMP 17 4.13Submission of updated EU-RMP documents. 18
5.DEFINITIONS 19 ANNEX A: Epidemiological methods for post-authorisation safety studies 22 1.STUDY DESIGNS 22 1.1Methods for active surveillance 22
1.1.1Sentinel sites 22
1.1.2Intensive Monitoring Schemes 22
1.1.3Prescription event monitoring 23
1.1.4Registries 23 1.
2.    Comparative Observational Studies 23
1.2.1.Cross-sectional study (survey) 23
1.2.2.Cohort study 23
1.2.3.Case-control study 24
1.2.4.Other novel designs 24 1.3.    Clinical Trials 25
1.3.1 Large Simple Trial 25 1.4.    Other studies 25
1.4.1.Occurrence of disease 25
1.4.
2.Drug utilisation study 26
2.DATA SOURCES 26 ANNEX B: methods for RISK MINIMISATION 28 1.RISK MINIMISATION 28 1.1Provision of information 28
1.1.1Additional Educational Material 28 1.2Legal Status of a Medicine 29 1.3Control at pharmacy level 30 1.4Control of prescription size or validity 30 1.5Informed consent and other patient aspects 30 1.6Restricted access programmes 30 1.7Patient registries 30 ANNEX C: EU-RMP TEMPLATE 32
1. INTRODUCTION
(BACKGROUND)
It is recognised that at the time of authorisation, information on the safety of a medicinal product is relatively limited.  This is due to many factors including the small numbers of subjects in clinical trials, restricted population in terms of age, gender and ethnicity, restricted co-morbidity, restricted co-medica
tion, restricted conditions of use, relatively short duration of exposure and follow up, and the statistical problems associated with looking at multiple outcomes.
A medicinal product is authorised on the basis that in the specified indication(s), at the time of authorisation, the benefit-risk is judged positive for the target population.  However, not all actual or potential risks will have been identified when an initial authorisation is sought.  In addition, there may be subsets of patients for whom the risk is greater than that for the target population as a whole.
Over the last few decades many important pharmacovigilance issues have been identified through spontaneous reporting of adverse reactions.  At the same time, consideration has been given to ways in which the current reporting systems might be augmented and strengthened. A strong contender is that planning of pharmacovigilance activities might be improved if it were more closely based on product specific issues identified from pre- or post-authorisation data and from pharmacological principles. Such planning would also guide the use of routine electronically collected data within health services to provide rapid investigation of predicted or emerging safety concerns.  This new proactive approach has now been recognised in the European Pharmaceutical Legislation including a specific reference to risk management.
The management of a single risk consists of four steps, risk detection, risk assessment, risk minimisation and risk communication. However, a typical individual medicinal product will have multiple risks attached to it and individual risks will vary in terms of severity, and individual patient and public health impact.  Therefore, the concept of risk management must also consider the combination of information on multiple risks with the aim of ensuring that the benefits exceed the risks by the greatest possible margin both for the individual patient and at the population level. Recently introduced legislation discusses the use of a risk management system but it does not define it.
A risk management system is defined in this guideline as a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicinal products, and the assessment of the effectiveness of those interventions.
This guideline aims to provide guidance on how Marketing Authorisation Holders (MAHs) and Applicants (MAAs) should meet the requirements for a description of a risk management system that they will introduce for an individual medicinal product, or a series of medicinal products,  in line with new Community legislation.  The guideline also describes how such a risk management system can be presented to Competent Authorities in the form of a Risk Management Plan.
Risk management is a continuing process throughout the lifetime of a medicinal product.  However, the activities used for risk management may be changed by technical, scientific and legislative developments, as well as by the information available, the perceived risks and their estimated public health impact and where a product is in its lifecycle. All these factors should be taken into account when formulating risk management plans in the EU.
2. SCOPE
EU legislation now requires MAA/MAHs to provide Competent Authorities with a description of pharmacovigilance and risk management systems.
The requirements and format for the description of a pharmacovigilance system are covered in “The guideline on monitoring of compliance with Pharmacovigilance regulatory obligations and Pharmacovigilance inspections for Centrally Authorised Products” and should be submitted in accordance with this guideline.
The present guideline provides guidance to Marketing Authorisation Applicants (MAAs) and Marketing Authorisation Holders (MAHs) in the European Union on how to meet the requirements for a ‘detailed description of the risk management system’ (section 4.1) and the circumstances when it is appropriate
(sections 4.3 and 4.13) to provide it.  The risks addressed in this Guideline are those related to non-clinical and clinical safety.  Where the disposal of the product might pose a particular risk because of remaining active substance (e.g. patches) this should also be addressed.  The Guideline is applicable to products in both the pre-authorisation and post-authorisation phases of either the centralised, decentralised or mutual recognition procedures.  It incorporates the concepts of the International Conference on Harmonisation (ICH) E2E Guideline.
BASIS
3. LEGAL
Article 6 of Regulation (EC) No 726/2004 and Article 8 of Directive 2001/83/EC lay down the particulars and documents to be included in an application for the authorisation of a medicinal product for human use.  More specifically and for the purpose of this guideline it requires in accordance with Article 8 (3)(ia) of Directive 2001/83/EC, as amended, the inclusion of “a detailed description of the pharmacovigilance and, where appropriate, of the risk management system which the applicant will introduce.” This provision forms the legal basis for this guideline.  The EU Risk Management Plan should be seen within the framework of the following provisions:
In the context of centrally authorised products Article 9 (4) of Regulation (EC) No 726/2004 requires for a favourable opinion that the following shall be attached to the Opinion:
b)“details of any conditions or restrictions which should be imposed on the supply or use of the medicinal product concerned, including conditions under which the medicinal product may be made available to the patients, in accordance with the criteria in Title VI of Directive 2001/83/EC”
c) “details of any recommended conditions or restrictions with regard to the safe and effective use of the medicinal product”
In addition to Article 9 (4) (c) above, Article 127 a) of Directive 2001/83/EC, as amended states that “When a medicinal product is to be authorised in accordance with Regulation (EC) 726/2004 and the Scientific Committee in its opinion refers to recommended conditions or restrictions with regard to the safe and effective use of the medicinal product […], a decision addressed to the Member States shall be adopted in accordance with the procedure provided for in Article 33 and 34 of the Directive, for the implementation of those conditions or restrictions”
The legislation provides for additional information to be requested from MAHs.
Article 23 of Regulation EC 726/2004 states  […] That qualified person shall reside in the Community and shall be responsible for the following:
c) ensuring that any request from the competent authorities for the provision of additional information necessary for the evaluation of the risks and benefits of a medicinal product is answered fully and

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