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22 January 2013 EMA/36988/2013 Guideline on good pharmacovigilance practices (GVP) Annex II – Templates: Direct Healthcare Professional Communication (DHPC) Draft finalised by the Agency in collaboration with Member States and submitted to ERMS FG 12 July 2012 Draft agreed by ERMS FG 20 July 2012 Draft adopted by Executive Director 25 July 2012 Start of public consultation 26 July 2012 End of consultation (deadline for comments) 21 September 2012 Revised draft finalised by the Agency in collaboration with Member States 10 January 2013 Revised draft agreed by ERMS FG 16 January 2013 Revised draft adopted by Executive Director as final 22 January 2013 Date for coming into effect 24 January 2013 See websites for contact details European Medicines Agency www.ema.europa.eu Heads of Medicines Agencies www.hma.eu The European Medicines Agency is an agency of the European Union © European Medicines Agency and Heads of Medicines Agencies, 2013. Reproduction is authorised provided the source is acknowledged. <Date> <Active substance, name of medicinal product and main message (e.g. introduction of a warning or a contraindication)> Dear Healthcare professional, <Name of marketing authorisation holder> would like to inform you of the following: Summary Style guide: This section should be in larger font size than the other sections of the DHPC and preferably in bullet points. • <Brief description of the safety concern, recommendations for risk minimisation (e.g. contraindications, warnings, precautions of use) and, if applicable, switch to alternative treatment> • <Recall information, if applicable, including level (pharmacy or patient) and date of recall> <A statement indicating that the information is being sent in agreement with the national competent authority or the European Medicines Agency, if applicable> Further information on the safety concern and the recommendations <Important details about the safety concern (adverse reaction, seriousness, statement on the suspected causal relationship, and, if known, the pharmacodynamic mechanism, temporal relationship, positive re-challenge or de-challenge, risk factors), also the reason for disseminating the DHPC at this point in time> <An estimation of the frequency of the adverse reaction or reporting rates with estimated patient exposure> <A statement indicating any association between the adverse reaction and off-label use, if applicable> <If applicable, details on the recommendations for risk minimisation> <Placing of the risk in the context of the benefit> <A statement on any previous DHPCs related to the current safety concern that have recently been distributed> <A schedule for follow-up action(s) by the marketing authorisation holder/competent authority, if applicable> Further information <Link/reference to other available relevant information, such as information on the website of a competent authority> <Therapeutic indication of the medicinal product, if not mentioned above> Call for reporting <A reminder of the need and how to report adverse reactions in accordance with the national spontaneous reporting system> <Mention if product is subject to additional monitoring and the reason why> Guideline on good pharmacovigilance practices (GVP) – Annex II - DHPC EMA/36988/2013 Page 2/3 <Details (e.g. name, postal address, fax number, website address) on how to access the national spontaneous reporting system> Company contact point <Contact point details for access to further information, including relevant website address(es), telephone numbers and a postal address> Annexes <Relevant sections of the Product Information that have been revised (with changes made visible)> <Detailed scientific information, if necessary> <List of literature references, if applicable> Guideline on good pharmacovigilance practices (GVP) – Annex II - DHPC EMA/36988/2013 Page 3/3

See websites for contact details European Medicines Agency www.ema.europa.eu Heads of Medicines Agencies www.hma.eu The European Medicines Agency is an agency of the European Union © European Medicines Agency and Heads of Medicines Agencies, 2014. Reproduction is authorised provided the source is acknowledged. 15 April 2014 EMA/876333/2011 Rev 3* Guideline on good pharmacovigilance practices (GVP) Annex I - Definitions (Rev 3) Date for coming into effect of first version 2 July 2012 Date for coming into effect of Revision 1 13 December 2012 Date for coming into effect of Revision 2 8 January 2014 Draft Revision 3* finalised by the Agency in collaboration with Member States 12 March 2014 Draft Revision 3 provided to ERMS FG 2 April 2014 Draft Revision 3 adopted by Executive Director as final 15 April 2014 Date for coming into effect of Revision 3* 28 April 2014 *Note: Revision 3 includes the following: - Amendments of definitions of Missing information (including its explanatory note) and Risk minimisation activity in accordance with revision 1 of GVP Module V. Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 2/24 Table of contents Abuse of a medicinal product ........................................................................................ 5 Advanced therapy medicinal product (ATMP) .................................................................. 5 Adverse event (AE); synonym: Adverse experience ......................................................... 5 Adverse event following immunisation (AEFI) ................................................................. 5 Adverse reaction; synonyms: Adverse drug reaction (ADR), Suspected adverse (drug) reaction, Adverse effect, Undesirable effect .................................................................... 5 Audit ......................................................................................................................... 5 Audit finding(s)........................................................................................................... 5 Audit plan .................................................................................................................. 6 Audit programme ........................................................................................................ 6 Audit recommendation ................................................................................................ 6 Clinical trial ................................................................................................................ 6 Closed signal .............................................................................................................. 6 Company core data sheet (CCDS) ................................................................................. 7 Company core safety information (CCSI) ....................................................................... 7 Compassionate use of a medicinal product ..................................................................... 7 Completed clinical trial ................................................................................................ 7 Consumer .................................................................................................................. 7 Crisis ......................................................................................................................... 7 Data lock point ........................................................................................................... 8 Development international birth date (DIBD) .................................................................. 8 Development safety update report (DSUR) ..................................................................... 8 Direct healthcare professional communication (DHPC) ..................................................... 8 EU reference date; synonym: Union reference date ......................................................... 8 Failure to vaccinate ..................................................................................................... 8 Generic medicinal product ............................................................................................ 9 Good pharmacovigilance practices (GVP) for the European Union ...................................... 9 Healthcare professional ............................................................................................... 9 Herbal medicinal product ............................................................................................. 9 Homeopathic medicinal product .................................................................................... 9 Identified risk ............................................................................................................. 9 Illegal purposes ........................................................................................................ 10 Immunological medicinal product ................................................................................ 10 Immunisation ........................................................................................................... 10 Immunisation anxiety-related reaction ........................................................................ 10 Immunisation error-related reaction ............................................................................ 11 Important identified risk and Important potential risk .................................................... 11 Important potential risk ............................................................................................. 11 Incident ................................................................................................................... 11 Individual case safety report (ICSR); synonym: Adverse (drug) reaction report ................ 12 International birth date (IBD) ..................................................................................... 12 Investigational drug .................................................................................................. 12 Investigational medicinal product ................................................................................ 12 Labelling .................................................................................................................. 12 Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 3/24 Medicinal product ...................................................................................................... 12 Medicinal product derived from human blood or human plasma ...................................... 12 Minimum criteria for reporting .................................................................................... 13 Missing information ................................................................................................... 13 Misuse of a medicinal product ..................................................................................... 13 Misuse of a medicinal product for illegal purposes ......................................................... 13 Name of the medicinal product ................................................................................... 13 Newly identified signal ............................................................................................... 13 Non-interventional trial; synonym: Non-interventional study .......................................... 14 Occupational exposure to a medicinal product .............................................................. 14 Off-label use ............................................................................................................ 14 Ongoing clinical trial .................................................................................................. 15 Ongoing signal ......................................................................................................... 15 Overdose ................................................................................................................. 15 Package leaflet ......................................................................................................... 15 Periodic safety update report (PSUR) ........................................................................... 15 Pharmacovigilance .................................................................................................... 15 Pharmacovigilance system ......................................................................................... 16 Pharmacovigilance system master file (PSMF) .............................................................. 16 Post-authorisation safety study (PASS) ........................................................................ 16 Potential risk ............................................................................................................ 16 Quality adherence ..................................................................................................... 16 Quality assurance ..................................................................................................... 17 Quality control and assurance ..................................................................................... 17 Quality improvements ............................................................................................... 17 Quality of a pharmacovigilance system ........................................................................ 17 Quality objectives ..................................................................................................... 17 Quality planning ....................................................................................................... 17 Quality requirements ................................................................................................. 17 Quality system of a pharmacovigilance system ............................................................. 17 Reference safety information ...................................................................................... 18 Registry ................................................................................................................... 18 Risk-benefit balance .................................................................................................. 18 Risk management plan (RMP) ..................................................................................... 18 Risk management system .......................................................................................... 18 Risk minimisation activity; synonym: Risk minimisation measure .................................... 18 Risks related to use of a medicinal product................................................................... 19 Safety concern ......................................................................................................... 19 Serious adverse reaction ............................................................................................ 19 Signal ...................................................................................................................... 19 Signal management process ....................................................................................... 20 Signal validation ....................................................................................................... 20 Solicited sources of individual case safety reports ......................................................... 20 Spontaneous report, synonym: Spontaneous notification ............................................... 20 Stimulated reporting ................................................................................................. 20 Substance ................................................................................................................ 21 Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 4/24 Summary of product characteristics (SmPC) ................................................................. 21 Target population (treatment); synonym: Treatment target population ........................... 21 Target population (vaccine); synonym: Vaccine target population ................................... 21 Traditional herbal medicinal product ............................................................................ 21 Unexpected adverse reaction ...................................................................................... 22 Upper management .................................................................................................. 22 Vaccination .............................................................................................................. 22 Vaccination failure .................................................................................................... 22 Vaccine .................................................................................................................... 22 Vaccine failure .......................................................................................................... 22 Vaccine pharmacovigilance......................................................................................... 23 Vaccine product-related reaction ................................................................................. 23 Vaccine quality defect-related reaction ........................................................................ 24 Valid individual case safety report ............................................................................... 24 Validated signal ........................................................................................................ 24 Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 5/24 Abuse of a medicinal product Persistent or sporadic, intentional excessive use of medicinal products which is accompanied by harmful physical or psychological effects [DIR 2001/83/EC Art 1(16)]. Advanced therapy medicinal product (ATMP) A medicinal product for human use that is either a gene therapy medicinal product, a somatic cell therapy product or a tissue engineered products as defined in Regulation (EC) No 1394/2007 [Reg (EC) No 1394/2077 Art 1(1)]. Adverse event (AE); synonym: Adverse experience Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment [Dir 2001/20/EC Art 2(m)]. An adverse event can therefore be any unfavourable and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Adverse event following immunisation (AEFI) See Vaccine pharmacovigilance, Vaccine product-related reaction, Vaccine quality defect-related reaction, Immunisation error-related reaction, Immunisation anxiety-related reaction Adverse reaction; synonyms: Adverse drug reaction (ADR), Suspected adverse (drug) reaction, Adverse effect, Undesirable effect A response to a medicinal product which is noxious and unintended [DIR 2001/83/EC Art 1(11)]1. Response in this context means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility (see Annex IV, ICH-E2A Guideline). Adverse reactions may arise from use of the product within or outside the terms of the marketing authorisation or from occupational exposure [DIR 2001/83/EC Art 101(1)]. Conditions of use outside the marketing authorisation include off-label use, overdose, misuse, abuse and medication errors. See also Adverse event, Serious adverse reaction, Unexpected adverse reaction, Off-label use, Overdose, Misuse of a medicinal product, Abuse of a medicinal product, Occupational exposure to a medicinal product Audit A systematic, disciplined, independent and documented process for obtaining audit evidence and evaluating it objectively to determine the extent to which the audit criteria are fulfilled (see ISO 19011 (3.1)2). Audit finding(s) Results of the evaluation of the collected audit evidence against audit criteria (see ISO19011 (3.4)3). 1 In the context of clinical trials, an adverse reaction is defined as all untoward and unintended responses to an investigational medicinal product related to any dose administered [Dir 2001/20/EC Art 2(n)]. 2 International Organization for Standardization (ISO); www.iso.org Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 6/24 Audit evidence is necessary to support the auditor’s results of the evaluation, i.e. the auditor’s opinion and report. It is cumulative in nature and is primarily obtained from audit procedures performed during the course of the audit. See also Audit Audit plan Description of activities and arrangement for an individual audit (see ISO19011 (3.12)4). See also Audit Audit programme Set of one or more audits planned for a specific timeframe and directed towards a specific purpose (see ISO 19011 (3.11)5). See also Audit Audit recommendation Describes the course of action management might consider to rectify conditions that have gone awry, and to mitigate weaknesses in systems of management control (see Sawyer LB et al, 20036). Audit recommendations should be positive and as specific as possible. They should also identify who is to act on them (Sawyer LB et al, 20036). See also Audit Clinical trial Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the objective of ascertaining its (their) safety and/or efficacy. This includes clinical trials carried out in either one site or multiple sites, whether in one or more Member State [Dir 2001/20/EC Art 2(a)]. See also Ongoing clinical trial, Completed clinical trial, Investigational medicinal product Closed signal In periodic benefit-risk evaluation reports, a signal for which an evaluation was completed during the reporting interval (see Annex IV, ICH-E2C(R2) Guideline). This definition is also applicable to periodic safety update reports. See also Signal 3 International Organization for Standardization (ISO); www.iso.org 4 International Organization for Standardization (ISO); www.iso.org 5 International Organization for Standardization (ISO); www.iso.org 6 Sawyer LB, Dittenhofer MA. Sawyer’s Internal Auditing. 5th ed. Altamonte Springs, FL: The IIA Research Foundation; 2003. Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 7/24 Company core data sheet (CCDS) For medicinal products, a document prepared by the marketing authorisation holder containing, in addition to safety information, material related to indications, dosing, pharmacology and other information concerning the product (see Annex IV, ICH-E2C(R2) Guideline). See also Company core safety information Company core safety information (CCSI) For medicinal products, all relevant safety information contained in the company core data sheet prepared by the marketing authorisation holder and which the marketing authorisation holder requires to be listed in all countries where the company markets the product, except when the local regulatory authority specifically requires a modification (see Annex IV, ICH-E2C(R2) Guideline). It is the reference information by which listed and unlisted are determined for the purposes of periodic reporting for marketed products, but not by which expected and unexpected are determined for expedited reporting (see Annex IV, ICH-E2C(R2) Guideline). See also Company core data sheet Compassionate use of a medicinal product Making a medicinal product available for compassionate reasons to a group of patients with a chronically or seriously debilitating disease or whose disease is considered to be life-threatening, and who cannot be treated satisfactorily by an authorised medicinal product (the medicinal product concerned must either be subject of an application for a central marketing authorisation or must be undergoing clinical trials) [REG (EC) No 726/2004 Art 83(2)]. Completed clinical trial Study for which a final clinical study report is available (see ICH-E2F Guideline, Volume 10 of the Rules Governing Medicinal Products in the EU). See also Clinical trial Consumer For the purpose of reporting cases of suspected adverse reactions, a person who is not a healthcare professional such as a patient, lawyer, friend or relative/parent/child of a patient (see Annex IV, ICH- E2D Guideline). Crisis In the context of the European Union Regulatory Network Incident Management Plan for Medicines for Human Use, a crisis is defined as a situation where, after assessment of the associated risks, urgent and coordinated action within the EU regulatory network is required to manage and control the situation (see European Union Regulatory Network Incident Management Plan for Medicines for Human Use7). See also Incident 7 www.ema.europa.eu Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 8/24 Data lock point For a periodic safety update report (PSUR), the date designated as the cut-off date for data to be included in a PSUR. For a periodic benefit-risk evaluation report (PBRER), the date designated as the cut-off date for data to be included in a PBRER, based on the international birth date (see Annex IV, ICH-E2C(R2) Guideline). For a development safety update report (DSUR), the date designated as the cut-off date for data to be included in a DSUR, based on the development international birth date (see ICH-E2F Guideline, Volume 10 of the Rules Governing Medicinal Products in the EU). Date includes day and month (see ICH-E2F Guideline, Volume 10 of the Rules Governing Medicinal Products in the EU). See also Periodic safety update report, Development safety update report, International birth date, Development international birth date Development international birth date (DIBD) Date of first approval (or authorisation) for conducting an interventional clinical trial in any country (see ICH-E2F Guideline, Volume 10 of the Rules Governing Medicinal Products in the EU). Development safety update report (DSUR) Format and content for periodic reporting on drugs under development (see ICH-E2F Guideline, Volume 10 of the Rules Governing Medicinal Products in the EU). Direct healthcare professional communication (DHPC) A communication intervention by which important information is delivered directly to individual healthcare professionals by a marketing authorisation holder or by a competent authority, to inform them of the need to take certain actions or adapt their practices in relation to a medicinal product. DHPCs are not replies to enquiries from healthcare professionals. EU reference date; synonym: Union reference date For medicinal products containing the same active substance or the same combination of active substances, the date of the first marketing authorisation in the EU of a medicinal product containing that active substance or that combination of active substances; or if this date cannot be ascertained, the earliest of the known dates of the marketing authorisations for a medicinal product containing that active substance or that combination of active substances [DIR 2001/83/EC Art 107c(5)]. Failure to vaccinate An indicated vaccine was not administered appropriately for any reason (see CIOMS-WHO8). For interpreting what is appropriate, consider the explanatory note for Immunisation error-related reaction. See also Vaccination failure 8 Council for International Organizations of Medical Sciences (CIOMS). Definition and application of terms of vaccine pharmacovigilance (report of CIOMS/WHO Working Group on Vaccine Pharmacovigilance). Genève: CIOMS; 2012. Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 9/24 Generic medicinal product A medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies [REG (EC) No 726/2004 Art 10(2)(b)]. Good pharmacovigilance practices (GVP) for the European Union A set of guidelines for the conduct of pharmacovigilance in the EU, drawn up based on Article 108a of Directive 2001/83/EC, by the European Medicines Agency in cooperation with competent authorities in Member States and interested parties, and applying to marketing authorisation holders in the EU, the Agency and competent authorities in Member States. Healthcare professional For the purposes of reporting suspected adverse reactions, healthcare professionals are defined as medically qualified persons, such as physicians, dentists, pharmacists, nurses and coroners (see Annex IV, ICH-E2D Guideline). Herbal medicinal product Any medicinal product, exclusively containing as active ingredients one or more herbal substances or one or more herbal preparations, or one or more such herbal substances in combination with one or more such herbal preparations [DIR 2001/83/EC Art 1(30)]. Herbal substances are all mainly whole, fragmented or cut plants, plant parts, algae, fungi, lichen in an unprocessed, usually dried, form, but sometimes fresh. Certain exudates that have not been subjected to a specific treatment are also considered to be herbal substances. Herbal substances are precisely defined by the plant part used and the botanical name according to the binominal system [DIR 2001/83/EC Art 1(31)]. Herbal preparations are preparations obtained by subjecting herbal substances to treatments such as extraction, distillation, expression, fractionation, purification, concentration or fermentation. These include comminuted or powered herbal substances, tinctures, extracts, essential oils, expressed juices and processed exudates [DIR 2001/83/EC Art 1(32)]. Homeopathic medicinal product Any medicinal product prepared from substances called homeopathic stocks in accordance with a homeopathic manufacturing procedure described by the European Pharmacopoeia or, in the absence thereof, by the pharmacopoeias currently used officially in the Member States. A homeopathic medicinal product may contain a number of principles [DIR 2001/83/EC Art 1(5)]. Identified risk An untoward occurrence for which there is adequate evidence of an association with the medicinal product of interest (see ICH-E2F Guideline, Volume 10 of the Rules Governing Medicinal Products in the EU). Examples include: • an adverse reaction adequately demonstrated in non-clinical studies and confirmed by clinical data; Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 10/24 • an adverse reaction observed in well-designed clinical trials or epidemiological studies for which the magnitude of the difference, compared with the comparator group on a parameter of interest suggests a causal relationship; • an adverse reaction suggested by a number of well-documented spontaneous reports where causality is strongly supported by temporal relationship and biological plausibility, such as anaphylactic reactions or application site reactions (see ICH-E2F Guideline, Volume 10 of the Rules Governing Medicinal Products in the EU). In a clinical trial, the comparator may be placebo, an active substance or non-exposure. Adverse reactions included in section 4.8 of the summary of product characteristics (SmPC) are also considered identified risks, unless they are class-related reactions which are mentioned in the SmPC but which are not specifically described as occurring with this product (these would normally be considered as a potential risk)). See also Risks related to use of a medicinal product, Important identified risk and Important potential risk, Missing information, Unexpected adverse reaction Illegal purposes See Misuse for illegal purposes Immunological medicinal product Any medicinal product consisting of vaccines, toxins, serums or allergen products: Vaccines, toxins and serums shall cover in particular agents used to produce active immunity (such as cholera vaccine, BCG, polio vaccine, smallpox vaccine), agents used to diagnose the state of immunity (including in particular tuberculin and tuberculin PPD, toxins for the Schick and Dick Tests, brucellin) and agents used to produce passive immunity (such as diphtheria antitoxin, anti-smallpox globulin, antilymphocytic globulin). Allergen products shall mean any medicinal product which is intended to identify or induce a specific acquired alteration in the immunological response to an allergizing agent [DIR 2001/83/EC Art 1(4)]. BCG stands for Bacillus Calmette-Guérin vaccine and PPD for purified protein derivative. Immunisation The process of making a person immune. For the context of Considerations P.I, immunisation refers to the process of making a person immune to an infection. See also Vaccination Immunisation anxiety-related reaction An adverse event following immunisation arising from anxiety about the immunisation (see CIOMS- WHO9). In this definition immunisation means the usage (handling, prescribing and administration) of a vaccine for the purpose of immunising individuals (see CIOMS-WHO9), which in the EU is preferably referred to as vaccination (in 9 Council for International Organizations of Medical Sciences (CIOMS). Definition and application of terms of vaccine pharmacovigilance (report of CIOMS/WHO Working Group on Vaccine Pharmacovigilance). Genève: CIOMS; 2012. Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 11/24 the report of CIOMS/WHO Working Group on Vaccine Pharmacovigilance the terms immunisation and vaccination are used interchangeably9). See also Adverse reaction, Vaccine pharmacovigilance, Vaccination Immunisation error-related reaction An adverse event following immunisation that is caused by inappropriate vaccine handling, prescribing or administration and thus by its nature is preventable (see CIOMS-WHO10). In this definition immunisation means the usage (handling, prescribing and administration) of a vaccine for the purpose of immunising individuals (see CIOMS-WHO10), which in the EU is preferably referred to as vaccination (in the report of CIOMS/WHO Working Group on Vaccine Pharmacovigilance the terms immunisation and vaccination are used interchangeably10). Inappropriate refers to usage (handling, prescribing and administration) other than what is licensed and recommended in a given jurisdiction based on scientific evidence or expert recommendations (see CIOMS-WHO10). See also Adverse reaction, Vaccine pharmacovigilance, Vaccination Important identified risk and Important potential risk An identified risk or potential risk that could have an impact on the risk-benefit balance of the product or have implications for public health (see ICH-E2F Guideline, Volume 10 of the Rules Governing Medicinal Products in the EU). What constitutes an important risk will depend upon several factors, including the impact on the individual, the seriousness of the risk and the impact on public health. Normally, any risk that is likely to be included in the contraindications or warnings and precautions section of the product information should be considered important (see Annex IV, ICH-E2C(R2) Guideline). See also Risk-benefit balance, Identified risk, Potential risk, Safety concern Important potential risk See Important identified risk and Important potential risk Incident A situation where an event occurs or new information arises, irrespective whether this is in the public domain or not, in relation to (an) authorised medicinal product(s) which could have a serious impact on public health. The incident may be related to quality, efficacy or safety concerns, but most likely to safety and/or quality (and possibly subsequent supply shortages). In addition, situations that do not seem at a first glance to have a serious impact on public health, but are in the public domain - subject of media attention or not- and may lead to serious public concerns about the product, may also need to be considered as incidents. Likewise, other situations which might have a negative impact on the appropriate use of a medicinal products (e.g. resulting in patients stop taking their medicine) may fall within the definition of an incident. In the context of this the European Union Regulatory Network Incident Management Plan for Medicines for Human Use Incident Management Plan, an incident relates to (a) medicinal product(s) authorised in the EU, irrespective of their route of authorisation. 10 Council for International Organizations of Medical Sciences (CIOMS). Definition and application of terms of vaccine pharmacovigilance (report of CIOMS/WHO Working Group on Vaccine Pharmacovigilance). Genève: CIOMS; 2012. Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 12/24 Individual case safety report (ICSR); synonym: Adverse (drug) reaction report Format and content for the reporting of one or several suspected adverse reactions to a medicinal product that occur in a single patient at a specific point of time11. See also Minimum criteria for reporting International birth date (IBD) The date of the first marketing authorisation for any product containing the active substance granted to any company in any country in the world (see Annex IV, ICH-E2C(R2) Guideline). Investigational drug Experimental product under study or development. This term is more specific than investigational medicinal product, which includes comparators and placebos (see ICH-E2F Guideline, Volume 10 of the Rules Governing Medicinal Products in the EU). See also Investigational medicinal product Investigational medicinal product An investigational medicinal product is a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorisation but used or assembled (formulated or packaged) in a way different from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form [Dir 2001/20/EC Art 2(d)]. See also Clinical trial Labelling Information on the immediate or outer packaging [DIR 2001/83/EC Art 1(25)]. Medicinal product Any substance or combination of substances • presented as having properties for treating or preventing disease in human beings; or • which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis [DIR 2001/83/EC Art 1(2)]. Medicinal product derived from human blood or human plasma Any medicinal product based on blood constituents which is prepared industrially by a public or private establishment, such as a medicinal product including, in particular, albumin, coagulating factor(s) and immunoglobulin(s) of human origin [DIR 2001/83/EC Art 1(10)]. 11 In the context of a clinical trial, an individual case is the information provided by a primary source to describe suspected unexpected serious adverse reactions related to the administration of one or more investigational medicinal products to an individual patient at a particular point of time. Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 13/24 Minimum criteria for reporting For the purpose of reporting cases of suspected adverse reactions, the minimum data elements for a case are: an identifiable reporter, an identifiable patient, an adverse reaction and a suspect medicinal product (see Annex IV, ICH-E2D Guideline). For the purpose of validation of individual case safety reports as qualifying for reporting in the EU, see Module VI. See also Individual case safety report Missing information Gaps in knowledge about a medicinal product, related to safety or use in particular patient populations, which could be clinically significant. It is noted that there is an ICH definition for important missing information, which is: critical gaps in knowledge for specific safety issues or populations that use the marketed product (see Annex IV, ICH-E2C(R2) Guideline). The change of the EU term, to name this concept “missing information” rather than “important missing information”, is to be clear that in the EU a marketing authorisation cannot be granted if there are unacceptable gaps in knowledge, in accordance with Article 12 of REG (EC) No 726/2004 a marketing authorisation shall be refused if the quality, safety or efficacy are not properly or sufficiently demonstrated. Misuse of a medicinal product Situations where the medicinal product is intentionally and inappropriately used not in accordance with the authorised product information. See also Misuse of a medicinal product for illegal purposes Misuse of a medicinal product for illegal purposes Misuse for illegal purposes is misuse with the additional connotation of an intention of misusing the medicinal product to cause an effect in another person. This includes, amongst others: the sale, to other people, of medicines for recreational purposes and use of a medicinal product to facilitate assault. See also Misuse of a medicinal product Name of the medicinal product The name which may be either an invented name not liable to confusion with the common name, or a common or scientific name accompanied by a trade mark or the name of the marketing authorisation holder [DIR 2001/83/EC Art 1(20)]. The common name is the international non-proprietary name (INN) recommended by the World Health Organization, or, if one does not exist, the usual common name [DIR 2001/83/EC Art 1(21)]. The complete name of the medicinal product is the name of the medicinal product followed by the strength and pharmaceutical form. Newly identified signal In periodic benefit-risk evaluation reports, a signal first identified during the reporting interval, prompting further actions or evaluation (see Annex IV, ICH-E2C(R2) Guideline). Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 14/24 This definition could also apply to a previously closed signal for which new information becomes available in the reporting interval prompting further action or evaluation (see Annex IV, ICH-E2C(R2) Guideline). This definition is also applicable to periodic safety update reports. See also Signal, Closed signal Non-interventional trial; synonym: Non-interventional study A study where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of collected data [Dir 2001/20/EC Art 2(c)]. Thus, a trial is non-interventional if the following requirements are cumulatively fulfilled: • the medicinal product is prescribed in the usual manner in accordance with the terms of the marketing authorisation; • the assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study; and • no additional diagnostic or monitoring procedures are applied to the patients and epidemiological methods are used for the analysis of collected data (see Volume 10 of the Rules Governing Medicinal Products in the EU, Questions & Answers Version 10.0). Non-interventional studies are defined by the methodological approach used and not by the scientific objectives. Non-interventional studies include database research or review of records where all the events of interest have already happened (this may include case-control, cross-sectional, cohort and other study designs making secondary use of data). Non-interventional studies also include those involving primary data collection (e.g. prospective observational studies and registries in which the data collected derive from routine clinical care), provided that the conditions set out above are met. In these studies, interviews, questionnaires and blood samples may be performed as normal clinical practice. Non-interventional trials do not fall in the scope of Directive 2001/20/EC. Occupational exposure to a medicinal product For the purpose of reporting cases of suspected adverse reactions, an exposure to a medicinal product as a result of one’s professional or non-professional occupation. Off-label use Situations where a medicinal product is intentionally used for a medical purpose not in accordance with the authorised product information. Off-label use includes use in non-authorised paediatric age categories. Unless specifically requested, it does not include use outside the EU in an indication authorised in that territory which is not authorised in the EU. Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 15/24 Ongoing clinical trial Trial where enrolment has begun, whether a hold is in place or analysis is complete, but for which a final clinical study report is not available (see ICH-E2F Guideline, Volume 10 of the Rules Governing Medicinal Products in the EU). See also Clinical trial, Completed clinical trial Ongoing signal In periodic benefit-risk evaluation reports, a signal that remains under evaluation at the data lock point (see Annex IV, ICH-E2C(R2) Guideline). This definition is also applicable to periodic safety update reports. See also Signal, Data lock point Overdose Administration of a quantity of a medicinal product given per administration or cumulatively which is above the maximum recommended dose according to the authorised product information. Clinical judgement should always be applied. Package leaflet A leaflet containing information for the user which accompanies the medicinal product [DIR 2001/83/EC Art 1(26)]. Periodic safety update report (PSUR) Format and content for providing an evaluation of the risk-benefit balance of a medicinal product for submission by the marketing authorisation holder at defined time points during the post-authorisation phase. In the EU, periodic safety update reports should follow the format described in Module VII. Pharmacovigilance Science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem (see WHO12). In line with this general definition, underlying objectives of pharmacovigilance in accordance with the applicable EU legislation for are: • preventing harm from adverse reactions in humans arising from the use of authorised medicinal products within or outside the terms of marketing authorisation or from occupational exposure; and • promoting the safe and effective use of medicinal products, in particular through providing timely information about the safety of medicinal products to patients, healthcare professionals and the public. Pharmacovigilance is therefore an activity contributing to the protection of patients’ and public health. 12 World Health Organization (WHO). The importance of pharmacovigilance: safety monitoring of medicinal products. Genève: WHO; 2002. Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 16/24 Pharmacovigilance system A system used by the marketing authorisation holder and by Member States to fulfil the tasks and responsibilities listed in Title IX of Directive 2001/83/EC and designed to monitor the safety of authorised medicinal products and detect any change to their risk-benefit balance [DIR 2001/83/EC Art 1(28d)]. In general, a pharmacovigilance system is a system used by an organisation to fulfil its legal tasks and responsibilities in relation to pharmacovigilance and designed to monitor the safety of authorised medicinal products and detect any change to their risk-benefit balance. Pharmacovigilance system master file (PSMF) A detailed description of the pharmacovigilance system used by the marketing authorisation holder with respect to one or more authorised medicinal products [DIR 2001/83/EC Art 1(28e)]. See also Pharmacovigilance system Post-authorisation safety study (PASS) Any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures [DIR 2001/83/EC Art 1(15)]. A post-authorisation safety study may be an interventional clinical trial or may follow an observational, non- interventional study design. See also Clinical trial, Non-interventional trial Potential risk An untoward occurrence for which there is some basis for suspicion of an association with the medicinal product of interest but where this association has not been confirmed (see ICH-E2F Guideline, Volume 10 of the Rules Governing Medicinal Products in the EU). Examples include: • non-clinical toxicological findings that have not been observed or resolved in clinical studies; • adverse events observed in clinical trials or epidemiological studies for which the magnitude of the difference, compared with the comparator group (placebo or active substance, or unexposed group), on the parameter of interest raises a suspicion of, but is not large enough to suggest, a causal relationship; • a signal arising from a spontaneous adverse reaction reporting system; • an event known to be associated with other active substances within the same class or which could be expected to occur based on the properties of the medicinal product (based on ICH-E2F Guideline, Volume 10 of the Rules Governing Medicinal Products in the EU). See also Adverse event, Signal Quality adherence Carrying out tasks and responsibilities in accordance with quality requirements [IR 520/2012 Art 8(3)]. See also Quality requirements Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 17/24 Quality assurance See Quality control and assurance Quality control and assurance Monitoring and evaluating how effectively the structures and processes have been established and how effectively the processes are being carried out [IR 520/2012 Art 8(3)]. This applies for the purpose of fulfilling quality requirements. See also Quality requirements Quality improvements Correcting and improving the structures and processes where necessary [IR 520/2012 Art 8(3)]. This applies for the purpose of fulfilling quality requirements. See also Quality requirements Quality of a pharmacovigilance system All characteristics of the pharmacovigilance system which are considered to produce, according to estimated likelihoods, outcomes relevant to the objectives of pharmacovigilance. See also Pharmacovigilance system, Quality system of a pharmacovigilance system Quality objectives See Quality requirements Quality planning Establishing structures and planning integrated and consistent processes [IR 520/2012 Art 8(3)]. This applies for the purpose of fulfilling quality requirements. See also Quality requirements Quality requirements Those characteristics of a system that are likely to produce the desired outcome, or quality objectives. See also Pharmacovigilance system, Quality system of a pharmacovigilance system Quality system of a pharmacovigilance system The organisational structure, responsibilities, procedures, processes and resources of the pharmacovigilance system as well as appropriate resource management, compliance management and record management [IR 520/2012 Art 8(2)]. The quality system is part of the pharmacovigilance system. See also Pharmacovigilance system, Quality of a pharmacovigilance system Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 18/24 Reference safety information In periodic benefit-risk evaluation reports for medicinal products, all relevant safety information contained in the reference product information (e.g. the company core data sheet) prepared by the marketing authorisation holder and which the marketing authorisation holder requires to be listed in all countries where it markets the product, except when the local regulatory authority specifically requires a modification (see Annex IV, ICH-E2C(R2) Guideline). It is a subset of information contained within the marketing authorisation holder’s reference product information for the periodic benefit-risk evaluation report. Where the reference product information is the company core data sheet, the reference safety information is the company core safety information (see Annex IV, ICH-E2C(R2) Guideline). See also Company core data sheet, Company core safety information Registry An organised system that uses observational methods to collect uniform data on specified outcomes in a population defined by a particular disease, condition or exposure. Risk-benefit balance An evaluation of the positive therapeutic effects of the medicinal product in relation to the risks [DIR 2001/83/EC Art 1(28a)], i.e. any risk relating to the quality, safety or efficacy of the medicinal product as regards patients’ health or public health [DIR 2001/83/EC Art 1(28)]. See also Risks related to use of a medicinal product Risk management plan (RMP) A detailed description of the risk management system [DIR 2001/83/EC Art 1(28c)]. To this end, it must identify or characterise the safety profile of the medicinal product(s) concerned, indicate how to characterise further the safety profile of the medicinal product(s) concerned, document measures to prevent or minimise the risks associated with the medicinal product, including an assessment of the effectiveness of those interventions and document post-authorisation obligations that have been imposed as a condition of the marketing authorisation [IR 520/2012 Art 30]. See also Risk management system, Risk minimisation activity Risk management system A set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to a medicinal product, including the assessment of the effectiveness of those interventions [DIR 2001/83/EC Art 1(28b)]. Risk minimisation activity; synonym: Risk minimisation measure An intervention intended to prevent or reduce the probability of the occurrence of an adverse reaction associated with the exposure to a medicine, or to reduce its severity should it occur. These activities may consist of routine risk minimisation (e.g. product information) or additional risk minimisation activities (e.g. healthcare professional or patient communications/educational materials). Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 19/24 Risks related to use of a medicinal product Any risk relating to the quality, safety or efficacy of the medicinal product as regards patients’ health or public health and any risk of undesirable effects on the environment [DIR 2001/83/EC Art 1(28)]. Safety concern An important identified risk, important potential risk or missing information. It is noted that the ICH definition of safety concern is: an important identified risk, important potential risk or important missing information, i.e. includes the qualifier “important” in relation to missing information (see Annex IV, ICH-E2C(R2) Guideline). The ICH-E2E Guideline (see Annex IV) uses the terms safety issue and safety concern interchangeably with the same definition for safety concern as defined in the ICH-E2C(R2) Guideline. See also Important identified risk and Important potential risk, Missing information Serious adverse reaction An adverse reaction which results in death, is life-threatening, requires in-patient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly/birth defect [DIR 2001/83/EC Art 1(12)]. Life-threatening in this context refers to a reaction in which the patient was at risk of death at the time of the reaction; it does not refer to a reaction that hypothetically might have caused death if more severe (see Annex IV, ICH-E2D Guideline). Medical and scientific judgement should be exercised in deciding whether other situations should be considered serious reactions, such as important medical events that might not be immediately life threatening or result in death or hospitalisation but might jeopardise the patient or might require intervention to prevent one of the other outcomes listed above. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or development of dependency or abuse (see Annex IV, ICH-E2D Guideline). Any suspected transmission via a medicinal product of an infectious agent is also considered a serious adverse reaction. See also Adverse reaction Signal Information arising from one or multiple sources, including observations and experiments, which suggests a new potentially causal association, or a new aspect of a known association between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action [IR 520/2012 Art 19(1)]. For the purpose of monitoring data in the EudraVigilance database, only signals related to an adverse reaction shall be considered [IR 520/2012 Art 19(1)]. For the purpose of Section 16.2 of the periodic benefit-risk evaluation report, signals relate to adverse effects (see Annex IV, ICH-E2C(R2) Guideline). See also Validated signal, Newly identified signal, Closed signal, Ongoing signal, Signal management process, Adverse reaction Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 20/24 Signal management process Includes the following activities: signal detection, signal validation, signal confirmation, signal analysis and prioritisation, signal assessment and recommendation for action [IR 520/2012 Art 21(1)]. It therefore is a set of activities performed to determine whether, based on an examination of individual case safety reports (ICSRs), aggregated data from active surveillance systems or studies, literature information or other data sources, there are new risks causally associated with an active substance or a medicinal product or whether known risks have changed. See also Signal validation Signal validation Process of evaluating the data supporting a detected signal in order to verify that the available documentation contains sufficient evidence demonstrating the existence of a new potentially causal association, or a new aspect of a known association, and therefore justifies further analysis of the signal [IR 520/2012 Art 21(1)]. See also Validated signal Solicited sources of individual case safety reports Organised data collection systems, which include clinical trials, registries, post-authorisation named- patients use programmes, other patient support and disease management programmes, surveys of patients or healthcare providers or information gathering on efficacy or patient compliance. For the purpose of safety reporting, solicited reports should not be considered spontaneous but classified as individual case safety reports from studies and therefore should have an appropriate causality assessment by a healthcare professional or the marketing authorisation holder (see Annex IV, ICH- E2D). See also Clinical trial, Post-authorisation safety study, Non-interventional trial Spontaneous report, synonym: Spontaneous notification An unsolicited communication by a healthcare professional or consumer to a company, regulatory authority or other organisation (e.g. the World Health Organization, a regional centre, a poison control centre) that describes one or more adverse reactions in a patient who was given one or more medicinal products and that does not derive from a study or any organised data collection scheme (see Annex IV, ICH-E2D). In this context, an adverse reaction refers to a suspected adverse reaction. Stimulated reporting can occur in certain situations, such as after a direct healthcare professional communication (DHPC), a publication in the press or questioning of healthcare professionals by company representatives, and adverse reaction reports arising from these situations are considered spontaneous reports (see Annex IV, ICH-E2D), provided the report meets the definition above. Reporting can also be stimulated by invitation from patients’ or consumers’ organisations to their members. Reporting made in the context of early post-marketing phase vigilance (EPPV), e.g. in Japan, is also considered stimulated reporting. See also Adverse reaction Stimulated reporting See Spontaneous report Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 21/24 Substance Any matter irrespective of origin which may be human (e.g. human blood and human blood products), animal (e.g. micro-organisms, whole animals, parts of organs, animal secretions, toxins, extracts, blood products), vegetable (e.g. micro-organisms, plants, part of plants, vegetable secretions, extracts), chemical (e.g. elements, naturally occurring chemical materials and chemical products obtained by chemical change or synthesis) [DIR 2001/83/EC Art 1(3)]. Summary of product characteristics (SmPC) Part of the marketing authorisation of a medicinal product setting out the agreed position of the product as distilled during the course of the assessment process which includes the information described in Article 11 of Directive 2001/83/EC. It is the basis of information for healthcare professionals on how to use the product safely and effectively. The package leaflet is drawn in accordance with the summary of product characteristics (based on A Guideline on Summary of Product Characteristics, Volume 2C of the Rules Governing Medicinal Products in the EU). Target population (treatment); synonym: Treatment target population The patients who might be treated with the medicinal product in accordance with the indication(s) and contraindications in the authorised product information. Target population (vaccine); synonym: Vaccine target population Persons who might be vaccinated in accordance with the indication(s) and contraindications in the authorised product information and official recommendations for vaccinations. Traditional herbal medicinal product A herbal medicinal product that fulfils the conditions laid down in Article 16a(1) of Directive 2001/83/EC [DIR 2001/83/EC Art 1(29)], i.e. (a) it has (an)indication(s) exclusively appropriate to traditional herbal medicinal products which, by virtue of their composition and purpose, are intended and designed for use without the supervision of a medical practitioner for diagnostic purposes or for prescription or monitoring of treatment; (b) it is exclusively for administration in accordance with a specified strength and posology; (c) it is an oral, external and/or inhalation preparation; (d) the period of traditional use as laid down in Article 16c(1)(c) has elapsed; (e) the data on the traditional use of the medicinal product are sufficient; in particular the product proves not to be harmful in the specified conditions of use and the pharmacological effects or efficacy of the medicinal product are plausible on the basis of long-standing use and experience [DIR 2001/83/EC Art 16a]. Regarding (d), the product must have been in medicinal use throughout a period of at least 30 years, including at least 15 years within the EU (see DIR 2001/83/EC Art 16c(c) and European Commission Questions & Answers Document on Registration of Traditional Herbal Medicinal Products, 2011). See also Herbal medicinal product Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 22/24 Unexpected adverse reaction An adverse reaction, the nature, severity or outcome of which is not consistent with the summary of product characteristics [DIR 2001/83/EC Art 1(13)]13. This includes class-related reactions which are mentioned in the summary of product characteristics (SmPC) but which are not specifically described as occurring with this product. For products authorised nationally, the relevant SmPC is that authorised by the competent authority in the Member State to whom the reaction is being reported. For centrally authorised products, the relevant SmPC is the SmPC authorised by the European Commission. During the time period between a CHMP opinion in favour of granting a marketing authorisation and the Commission decision granting the marketing authorisation, the relevant SmPC is the SmPC annexed to the CHMP opinion. See also Summary of product characteristics Upper management Group of persons in charge of the highest executive management of an organisation. Membership of this group is determined by the governance structure of the organisation. While it is envisaged that the upper management usually is a group, the head of the organisation is the one person at the top of the organisation with ultimate responsibility for ensuring that the organisation complies with relevant legislation. Vaccination The administration of a vaccine with the aim to produce immune response. See also Immunisation Vaccination failure Vaccination failure due to actual vaccine failure or failure to vaccinate (see CIOMS-WHO14). Vaccination failure may be defined based on clinical endpoints or immunological criteria, where correlates or surrogate markers for disease protection exist. Primary failure (e.g. lack of seroconversion or seroprotection) needs to be distinguished from secondary failure (waning immunity) (see CIOMS-WHO14). See also Vaccine failure, Failure to vaccinate Vaccine See Immunological medicinal product Vaccine failure Confirmed or suspected vaccine failure. Confirmed clinical vaccine failure Occurrence of the specific vaccine-preventable disease in a person who is appropriately and fully vaccinated taking into account the incubation period and the normal delay for the protection to be acquired as a result of immunisation (see CIOMS-WHO15). 13 For investigational medicinal products, an unexpected adverse reaction is an adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g. the investigator’s brochure for an unauthorised investigational product or the summary of product characteristics for an authorised product) [Dir 2001/20/EC Art 2(p)]. 14 Council for International Organizations of Medical Sciences (CIOMS). Definition and application of terms of vaccine pharmacovigilance (report of CIOMS/WHO Working Group on Vaccine Pharmacovigilance). Genève: CIOMS; 2012. Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 23/24 Suspected clinical vaccine failure Occurrence of disease in an appropriately and fully vaccinated person, but the disease is not confirmed to be the specific vaccine-preventable disease, e.g. disease of unknown serotype in a fully vaccinated person (based on CIOMS-WHO15). Confirmed immunological vaccine failure Failure of the vaccinated person to develop the accepted marker of protective immune response after being fully and appropriately vaccinated, as demonstrated by having tested or examined the vaccinated person at an appropriate time interval after completion of immunisation (based on CIOMS- WHO15). Suspected immunological vaccine failure Failure of the vaccinated person to develop the accepted marker of protective immune response after being fully and appropriately vaccinated, but with the testing or examination of the vaccinated person done at an inappropriate time interval after completion of immunisation (based on CIOMS-WHO15). For interpreting what means appropriately vaccinated, consider the explanatory note for Immunisation error-related reaction. See also Vaccination failure Vaccine pharmacovigilance The science and activities relating to the detection, assessment, understanding and communication of adverse events following immunisation and other vaccine- or immunisation-related issues, and to the prevention of untoward effects of the vaccine or immunisation (see CIOMS-WHO16). In this definition, immunisation means the usage of a vaccine for the purpose of immunising individuals (see CIOMS-WHO16), which in the EU is preferably referred to as vaccination (in the report of CIOMS/WHO Working Group on Vaccine Pharmacovigilance the terms immunisation and vaccination are used interchangeably16). Usage includes all processes that occur after a vaccine product has left the manufacturing/packaging site, i.e. handling, prescribing and administration of the vaccine (see CIOMS-WHO16). An adverse event following immunisation (AEFI) is any untoward medical occurrence which follows immunisation and which does not necessarily have a causal relationship with the usage of the vaccine. The adverse event may be any unfavourable or unintended sign, abnormal laboratory finding, symptom or disease. While this AEFI definition is compatible with the definition of adverse event applied in the EU, the AEFI definition is not needed to describe pharmacovigilance for vaccines in the EU. However, EU guidance on pharmacovigilance for vaccines makes use of the terminology suggested by CIOMS-WHO16 regarding possible causes of adverse events, turning them into suspected adverse reactions. A coincidental event is an AEFI that is caused by something other than the vaccine product, immunisation error or immunisation anxiety (see CIOMS-WHO16). See also Adverse event, Immunisation anxiety-related reaction, Immunisation error-related reaction, Vaccine product-related reaction, Vaccine quality defect-related reaction, Vaccination Vaccine product-related reaction An adverse event following immunisation that is caused or precipitated by a vaccine due to one or more of the inherent properties of the vaccine product (see CIOMS-WHO17). 15 Council for International Organizations of Medical Sciences (CIOMS). Definition and application of terms of vaccine pharmacovigilance (report of CIOMS/WHO Working Group on Vaccine Pharmacovigilance). Genève: CIOMS; 2012. 16 Council for International Organizations of Medical Sciences (CIOMS). Definition and application of terms of vaccine pharmacovigilance (report of CIOMS/WHO Working Group on Vaccine Pharmacovigilance). Genève: CIOMS; 2012. Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3) EMA/876333/2011 Rev 3 Page 24/24 In this definition immunisation means the usage (handling, prescribing and administration) of a vaccine for the purpose of immunising individuals (see CIOMS-WHO17), which in the EU is preferably referred to as vaccination (in the report of CIOMS/WHO Working Group on Vaccine Pharmacovigilance the terms immunisation and vaccination are used interchangeably17). See also Adverse reaction, Vaccine pharmacovigilance Vaccine quality defect-related reaction An adverse event following immunisation that is caused or precipitated by a vaccine that is due to one or more quality defects of the vaccine product including its administration device as provided by the manufacturer (see CIOMS-WHO18). In this definition immunisation means the usage (handling, prescribing and administration) of a vaccine for the purpose of immunising individuals (see CIOMS-WHO18), which in the EU is preferably referred to as vaccination (in the report of CIOMS/WHO Working Group on Vaccine Pharmacovigilance the terms immunisation and vaccination are used interchangeably18). For the purpose of this definition, a vaccine quality defect is defined as any deviation of the vaccine product as manufactured from its set quality specifications (see CIOMS-WHO18). See also Adverse reaction, Vaccine pharmacovigilance Valid individual case safety report See Individual case safety report Validated signal A signal where the signal validation process of evaluating the data supporting the detected signal has verified that the available documentation contains sufficient evidence demonstrating the existence of a new potentially causal association, or a new aspect of a known association, and therefore justifies further analysis of the signal [based on IR 520/2012 Art 21(1)]. See also Signal (summing up to 104 definitions) 17 Council for International Organizations of Medical Sciences (CIOMS). Definition and application of terms of vaccine pharmacovigilance (report of CIOMS/WHO Working Group on Vaccine Pharmacovigilance). Genève: CIOMS; 2012. 18 Council for International Organizations of Medical Sciences (CIOMS). Definition and application of terms of vaccine pharmacovigilance (report of CIOMS/WHO Working Group on Vaccine Pharmacovigilance). Genève: CIOMS; 2012.

1 7th Stakeholder Forum 27. September 2013 Am 27. September 2013 fand in den Räumen der EMA die inzwischen siebte Sitzung des Stakeholder Forums statt, bei dem regelmäßig über die Fortschritte in der Um- setzung der geänderten EU-Regelungen zur Pharmakovigilanz berichtet wird. Einem ausführlichen Sachstandsbericht der EMA (Dr. Peter Arlett) zur Implementie- rung der Neuregelungen folgten Beiträge der Stakeholder (Vertreter der Mitgliedstaa- ten, der Industrie, von Patientenorganisationen und Angehörigen der Gesundheitsbe- rufe). Die wichtigsten Ergebnisse sind nachfolgend zusammengefasst. Status der GVP-Module Folgende Module sind noch nicht fertiggestellt: - Modul XI - Public participation Status: Veröffentlichung zur Kommentierung geplant für Q2/2014 - Modul XII - Continuous pharmacovigilance Status: Veröffentlichung zur Kommentierung geplant für Q2/2014 - Modul XIV - International cooperation Status: Veröffentlichung zur Kommentierung geplant für Q1/2014 Die überarbeiteten Module VI, VII und VI sollen noch bis Ende 2013 veröffentlicht werden. RMPs - Zwischen September 2012 und Juni 2013 wurden 374 RMPs bewertet PSURs - Single assessment unter Beteiligung des PRAC findet statt für Substanzen mit nur oder auch zentralen Zulassungen (EURD-Liste), noch nicht für nationale (MRP/DCP)-Zulassungen - PSUR-Bewertungen führten im Zeitraum von Dezember 2012 bis Juni 2013 weder zum Rückruf einer Zulassung noch zur Anordnung eines Ruhens der Zulassung 2 PASS und PAES - Seit Juli 2012 wurden 135 Studien im EU PASS Register registriert - Derzeit wird ein Prozess entwickelt, der es MAHs ermöglicht, eine PASS, die mehrere Produkte betrifft, gemeinsam durchzuführen - Ein wissenschaftlicher Leitfaden für methodische Aspekte der Durchführung von PAES soll in einem Experten-Workshop vom 24. bis 25. Oktober 2013 erstellt werden Artikel 57(2): Electronic submission of core medicine information - Bisher wurden 443.000 Arzneimittel-Einträge registriert - Diskussion der nächsten Schritte in einem weiteren Workshop am 23. Oktober 2013 Signale Seit September 2012 wurden 92 Signale detektiert. Folgende Ergebnisse wurden bisher vom PRAC beschlossen. - 5 Empfehlungen für ein Referral - 32 Forderungen einer Variation - 51 Forderungen für ein kumulatives Review Eine Liste der seit September 2012 im PRAC diskutierten Signale soll in Kürze auf der EMA-Webseite veröffentlicht werden. Außerdem ist geplant im Oktober 2013 ein Q&A-Dokument bezüglich der PRAC-Empfehlungen zu Signalen zu veröffentlichen. Additional monitoring - Die Liste umfasst derzeit 119 Substanzen und wird monatlich überarbeitet - Die EMA hat ein Video zur Erklärung des schwarzen Symbols und der zusätz- lichen Überwachung sowie Informationsmaterial für Patienten veröffentlicht Referrals - Von Juli 2012 bis Juli 2013 wurden 5 Artikel 107i und 11 Artikel 31-Verfahren gestartet - In den PRAC-Meetings nehmen die Diskussionen zu Referrals (33%) und zu RMPs (19%) den meisten zeitlichen Raum ein - Dauer der Referral-Prozesse ist verkürzt: die finalisierten Referrals (nach den Artikeln 20, 31, 107i), die vom PRAC bearbeitet wurden, dauerten zwischen ein und acht Monaten. Von insgesamt 21 Verfahren wurden bisher 9 Verfah- ren finalisiert 3 Transparenz und Kommunikation Beispielsweise: - Veröffentlichung von Agenda, Meeting-Highlights, Safety referrals und Proto- kolle der PRAC-Meetings - Veröffentlichung von RMP-Summaries: Pilotphase startet im Oktober 2013 - Workshops, Implementation Working Groups, Stakeholder Meetings mit den Beteiligten - Verpflichtung für MAHs, die EMA-Webseite bzw., wenn fertiggestellt, das EU Medicines Webportal regelmäßig zu sichten (s.u.) EudraVigilance - Zahl der Einzelfallmeldungen ist nach den Neuregelungen deutlich angestie- gen - Datenqualität soll verbessert werden, beispielsweise sind rund 100.000 Dupli- kate eliminiert und rund 80.000 Begriffe in Fallberichten rekodiert worden Als größte Herausforderungen im Rahmen der gesamten Umsetzung benannte Peter Arlett den Umfang der Änderungen auf der einen Seite und die dem gegenüber stark begrenzten Ressourcen (bei der EMA) sowie die Tatsache, dass die Regelungen den gesamten Lebenszyklus eines Produkts betreffen und dass eine große Anzahl von „Stakeholdern“ an der Umsetzung der Neuregelungen beteiligt bzw. davon be- troffen ist. Eine Vielzahl von Funktionalitäten und angekündigten Aktivitäten bzw. Services der EMA steht zum jetzigen Zeitpunkt noch nicht zur Verfügung. Dazu ge- hört beispielsweise eine zentrale Literaturrecherche, die vollständige und getestete bzw. auditierte Funktionsfähigkeit von EudraVigilance für zentrale Einzelfall- Meldungen, das PSUR-Repository, eine Nutzbarkeit des Artikel 57(2)-Tools incl. von Update-Daten der Industrie. Außerdem steht noch die Errichtung des in der Gesetz- gebung geforderten „EU Medicines Web-portal“ aus. Die EMA weist in diesem Zu- sammenhang daraufhin, dass in der Zwischenzeit die EMA-Webseite als solches fungiert. Die Präsentation unseres europäischen Dachverbandes AESGP im Rahmen der Sit- zung ist im Mitgliederbereich der BAH-Homepage abrufbar unter > Pharmakovigilanz > EU-Pharmakovigilanz > Stakeholder Meetings Bonn, 4. Oktober 2013

An agency of the European Union Implementing the pharmacovigilance legislation: focus on EU level activities 7th Stakeholders forum on the implementation of the new Pharmacovigilance legislation Peter Arlett, Pharmacovigilance Department, EMA 27 September 2013 In this presentation 1. Objectives, where we have come from: where we are going 2. What has been delivered in 2012 – 2013 and what are now routine activities 3. What remains to be done 4. Moving forward together 1 2 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2003: EC decision to undertake an assessment of the Community system of pharmacovigilance 2005: Independent study completed to map the strengths and weaknesses of the EU system 2007: Commission strategy to strengthen and rationalise pharmacovigilance 2006-2008: Research, consultation, policy development December 2008: ‘Pharma package’ (Pharmacovigilance, Information to patients and falsified medicines) adopted by the European Commission and transmitted to Council and European Parliament to start the co-decision procedure for pharmacovigilance December 2008 - 22 September 2010: Co-decision procedure until final favourable vote in the European Parliament 31 December 2010: Publication of Regulation (EC) 726/2004 and Directive 2001/83/EC (entry into force in July 2012). 25 October 2012: Publication of Regulation (EC) 1027/2012 and Directive 2012/26/EU (entry into force in June and October 2013). Where we have come from Where we are going: legislation objectives Promote and protect public health by reducing burden of Adverse Drug Reactions and optimising the use of medicines: • Clear roles and responsibilities • Science based • Risk based/proportionate • Increased proactivity/planning • Reduced duplication/redundancy • Integrate benefit and risk • Ensure robust and rapid EU decision-making • Strengthen the EU Network • Engage patients and healthcare professionals • Increase transparency and accountability • Provide better information on medicines 3 Challenges • Major resource constraints • Size of change • Product lifecycle impacted • Number of stakeholders impacted 4 Commission implementing regulation (EU) No 520/2012 • Legally binding • 9 Chapters 5 Commission Implementing Regulation (EU) No 520/2012 Chapter I Pharmacovigilance System Master File Chapter II Minimum requirements for the quality systems for the performance of pharmacovigilance activities Chapter III Minimum requirements for the monitoring of data in the Eudravigilance database Chapter IV Use of terminology, formats and standards Chapter V Transmission of reports of suspected adverse reactions Chapter VI Risk Management Plans Chapter VII Periodic Safety Update Reports Chapter VIII Post-authorisation Safety Studies Chapter IX Final provisions Good pharmacoVigilance Practice (GVP) 6 •Self-standing guidance on pharmacovigilance replacing Volume 9A •Addressed to EU Marketing Authorisation Holders, Competent Authorities in Member States and Agency •Developed within EU network •8 weeks public consultation •2 types of ‘Chapters’: •Modules for major processes •Product or populations specific (P) •GVP structure: •A: Introduction •B: Structures and processes •C: Operation of the EU network Good pharmacoVigilance Practice (GVP) Module I Pharmacovigilance systems and their quality systems Module II Pharmacovigilance system master file Module III Pharmacovigilance inspections Module IV Pharmacovigilance audits Module V Risk management systems Module VI Management and reporting of ADRs Publication of Revision 1 as final Q4 2013 Module VII Periodic safety update reports Publication of Revision 1 as final Q4 2013 Module VIII Post-authorisation safety studies Module IX Signal management Module X Additional monitoring Module XI Public participation Public consultation Q2 2014 Module XII Continuous pharmacovigilance Public consultation Q1 2014 Module XIV International cooperation Public consultation Q1 2014 Module XV Safety communication Under development Public consultation Published P I – Vaccines Publication as final Q4 2013 Module XVI Risk minimisation measures Publication as final Q4 2013 Prioritised implementation agreed by EMA Management Board in December 2011 and 2012 7 Not started On-going implementation Implemented What has been delivered and what is now routine While date period for most of the slides relates to July 2012 to July 2013, a small number of slides use a different data period 8 Prioritised implementation of the pharmacovigilance legislation 9 Collection of key information on medicines RMP data 10 RMP Data 11 12 Prioritised implementation of the pharmacovigilance legislation 13 14 PSURs: Outcomes at PRAC 14 17 33 25 30 43 38 19 205 3 2 5 2 8 9 9 38 0 50 100 150 200 250 Dec-12 Jan-13 Feb-13 Mar-13 Apr-13 May-13 Jun-13 Total Maintenance CHMP Variation Suspension Revocation • 243 PSUR PRAC recommendations (single CAPs) from Dec 2012 till June 2013 • 38 (16%) PRAC recommendations to vary MA • No suspensions, no revocations 15 PSURs: Observations • Procedure now better understood by all concerned parties – clear improvements noted. • Increasing number of PSUR procedures leading directly to MA variation – efficiency gains since no need for follow-up variation and health gains through rapid update of product information • Still room for further improvement in terms of better understanding the new procedure: – For regulators:  requests for additional information to be more clearly phrased  requests for labelling to be explicit and clearly justified – For pharmaceutical industry: key success factor is the provision by companies of clear positions and proposals for regulatory action/follow-up Further training to be provided 16 16 Prioritised implementation of the pharmacovigilance legislation Collection of key information on medicines 16 17 135 studies registered: most since July 2012 18 18 Prioritised implementation of the pharmacovigilance legislation Collection of key information on medicines 18 Article 57(2) data content Reference Terminology: -R1: Pharmaceutical form -R2: Route of Administration -R3: ATC codes -R4: Units of Measurement -R5: Units of presentation -R6: Reference source Substance Information: - S1: Substance names - S2: Substance Translations - S3: Substance synonyms - S4: Substance class - S5: Reference source - S6: International Codes Structured Medicinal Product Information: - P1: MAH (Legal Entity) - P2: QPPV - P3: PhV Enquiries - P4: PSMF - P5: Authorisation country code - P6: Authorisation procedure - P7: Authorisation status - P8: Authorisation number - P9: Authorisation date - P10: MRP/DCP/EU number - P11: Date of withdrawal/revocation/suspension - P12: Package description - P13: Orphan drug designation - P14: Comments (e.g. paediatric use) - P15: Medicinal product name - P16: Medicinal product invented name - P17: Product generic name - P18: Product company name - P19: Product strength name - P20: Product form name - P21: Pharmaceutical Form - P22: Route of administration(s) - P23: Active ingredient(s), Adjuvant(s) - P24: Excipients - P25: Medical device(s) - P26: Strength of active ingredient(s)/adjuvant(s) - P27: Therapeutic Indication(s) - P28: ATC code Unstructured Medicinal Product Information: - P29: Summary of Medicinal Product Characteristics Organisation information: -O1: MAH (Legal Entity) -O2: QPPV -O3: PhV Enquiries -O4: PhV System Master File Business Service Product P Business Service Substance S Business Service Organisation Business Service Referential s O R 19 Article 57(2) data: business case • Better analysis and understanding of data/information – EudraVigilance data analysis, safety signal detection • Regulatory action to safeguard public health – Support to referral procedures (e.g. interaction with MAHs) – Provision of other PRAC outputs to MAHs – Facilitation of PhV inspections – Longer term (ISO) – quality defects of medicines and counterfeits can be linked to the correct products 20 Article 57(2) data: business case • Communication with stakeholders – European medicines web portal (search for all human medicines authorised in the EU) – Publication of lists (work-sharing purposes, products under additional monitoring, PSUR list, list of withdrawn products) – Access to EudraVigilance data (proactive and reactive) – EU/international data exchange 21 22 Article 57(2) Implementation status • As of 23rd September, MAHs have submitted a total of 443,000 medicinal product entries to the Agency. • New entries in the XEVMPD are received on a daily basis 23 Strategy for achieving reliable Article 57(2) data • Two step approach is envisaged: – Longer term: achieve QA (quality assurance) built into the overall process, alongside targeted ex-post controls – Short to medium term: built on current* QA activities complemented with QC (quality control) * Note • Systematic semi-automatic monitoring via SAS routines of the new/updated received data • Publication of detailed submission guidances • Free training to stakeholders • Dedicated helpdesk system • Comparisons with references sources (e.g. SmPC) • Monitoring/evaluation of (limited) received feedback from stakeholders 24 Article 57(2) Substance data Quality Control Substance Information: - S1: Substance names - S2: Substance Translations - S3: Substance synonyms - S4: Substance class - S5: Reference source - S6: International Codes Business Service Substance S This is one of the initial Quality Control activities started by the Agency to improve the quality of the Art57 submissions Two aspects need to be considered: • De-duplication of substance names • Completion of substance information content Currently the EMA is focusing on the first aspect above: De- duplication of substance names 25 Next Steps The next steps in the Art57 implementation, including strategy and timelines for the kick-off of the maintenance phase, will be presented and discussed with the EU Pharmaceutical Industry Associations in the Art57 Implementation Working Group on 23 October 2013. Summary of the discussion will be published soon after the meeting. Supporting the wider EU data architecture strategy….. Integrated Data Architecture Extension of the Data Architecture Roadmap to cover other entities 26 Industry & other stakeholders National Competent Authorities European Medicines Agency B us in es s Pr oc es se s S er vi ce s Substance Data Mgt Product Data Mgt Organisation Data Mgt Referentials Data Mgt Clinical Trials Marketing Authorisation Pharmacovigilance Manufacturing … D at a S P O R CT MA PhV Mfg … Prioritised implementation of the pharmacovigilance legislation Collection of key information on medicines 27 Spontaneous reporting by patients in EEA 28 0 5000 10000 15000 20000 25000 Patient reporting Pre Leg* Patient reporting after Leg** 15407 24798 * Pre legislation data period - 02/07/2011 - 01/07/2012 ** Post legislation data period -02/07/2012 - 01/07/2013 Reporting numbers: Pre and Post legislation 29 Prioritised implementation of the pharmacovigilance legislation 30 31 31 Prioritised implementation of the pharmacovigilance legislation Better analysis/understanding of data and information 31 Achievements of EV Data Quality management 07/2012 – 07/2013 • Recoding of medicinal product terms reported in safety reports: 87,388 terms recoded • Duplicate detection & management of individual safety reports: 101,800 duplicate cases removed from the system • EudraVigilance Data Quality Assessments: 242 assessments performed and senders (MAHs/Sponsors/NCAs) provided feedback 32 33 Signals: Data and PRAC Outcomes 33 7 9 5 3 4 3 2 4 10 4 2 1 2 4 2 5 3 3 5 5 1 1 2 1 0 2 4 6 8 10 12 14 16 Sep-12 Oct-12 Nov-12 Dec-12 Jan-13 Feb-13 Mar-13 Apr-13 May-13 Jun-13 PRAC Recommendation for a referral PRAC Request for Variation PRAC Request for cumulative review PRAC recommendation for a referral PRAC request for variation PRAC request for cumulative review Signal descriptions – first publication in coming days 34 Prioritised implementation of the pharmacovigilance legislation Better analysis of data and information 35 The current number of the additionally monitored drugs – 119 (published 9 August 2013) 95 100 105 110 115 120 Jun-13 Jul-13 Aug-13 106 111 119 Jun-13 Jul-13 Aug-13 Sep-13 Additional monitoring • Mandatory for following products:  Medicines containing a new active substance authorised after 1 January 2011  Any biological medicinal product authorised after 1 January 2011  Conditional or exceptional conditions of marketing  Obligation for post authorisation safety studies  Stricter reporting of adverse reactions • EMA publishes the list 37 ‘Black symbol’ for products under additional monitoring (1/2) • Black symbol: – Selected by the European Commission following a recommendation of the PRAC (after involving stakeholders) on 7 March 2013 – Inverted equilateral black triangle • New text in Product Information – SPC text: <{Black symbol}> This medicinal product is subject to additional monitoring. This is to allow any safety information to be identified rapidly. Healthcare professionals are encouraged to report any suspected adverse reactions. See section 4.8.> – PL text: <{Black symbol} This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. • List of products under additional monitoring – initial list published on 25th April 2013 and updated every month New communication material on additional monitoring (1/2) 38 38 Factsheet + Video • Consultation: EC, HMA WGCP and Project Team 3 involved in preparation • PRAC informed at September meeting • All EU languages • Easily printable • Based on already published information Prioritised implementation of the pharmacovigilance legislation 39 Better analysis/understanding of data and information 40 41 41 Prioritised implementation of the pharmacovigilance legislation Regulatory action to safeguard public health 41 42 PRAC volumes (July 2012 – July 2013) 1 2 4 2 7 5 8 1 1 3 2 2 2 1 13 15 13 10 8 10 7 13 17 13 7 3 10 34 50 57 64 50 60 45 61 0 20 35 30 33 51 53 31 33 1 4 2 3 6 6 5 13 16 3 4 2 0 2 1 2 1 3 0 4 8 5 6 5 6 11 15 11 0 20 40 60 80 100 120 140 160 180 Sep-12 Nov-12 Jan-13 Mar-13 May-13 Jul-13 Other safety issues - MS Other safety issues - CHMP PhVig Inspections PASS PSURs RMPs Signals Art.5(3) referrals 43 44 Prioritised implementation of the pharmacovigilance legislation Regulatory action to safeguard public health 45 46 Referrals: Data 46 • Number of referrals (July 2012 – July 20131): 1 Also includes procedures started and finalised by PRAC in July 2013 2 In 6 procedures (29%) an ad-hoc expert meeting has been organised 3 Finalised means final outcome obtained at either CHMP or CMDh 46 Referral type Started Finalised Art. 20 5 3 Art. 107i 5 3 Art. 31 11 3 Total 212 93 47 Referrals: Outcomes • Overview of finalised referrals: • Time taken: 1 to 8 months 47 Procedure name Article Finalised Committee Grounds Outcome EC Decision Duration (calender days) Tredaptive 20 Jan-13 CHMP B-R Suspension Yes 1 month Trevaclyn 20 Jan-13 CHMP B-R Suspension Yes 1 month Pelzont 20 Jan-13 CHMP B-R Suspension Yes 1 month Tetrazepam 107i Apr-13 CMDh S Suspension Yes 3 months Cyproterone, ethinylestradiol - DIANE 35 & other medicines containing cyproterone acetate 2mg and ethinylestradiol 35 micrograms 107i May-13 CMDh S Variation Yes 3 months Almitrine 31PhV May-13 CMDh B-R Revocation No 7 months Codeine-containing medicinal products 31PhV Jun-13 CMDh B-R Variation No 8 months Diclofenac-containing medicinal products 31PhV Jun-13 CMDh B-R Variation Yes 8 months Flupirtine 107i Jun-13 CMDh S Variation Yes 6 months 48 Referrals: Observations • Positive experience: – High acceptance rate by CHMP/CMDh of PRAC outcome – Compliance with legal deadlines – Shortening of scientific review process for Art 31 procedures – Excellent teamwork EMA Secretariat – PRAC Rapporteurs (in terms of procedural, content and data support aspects) • Issues requiring consideration: – Optimal use of referrals tools for public health – Workload for Network high and remains unpredictable – Communication and planning: Need to continue to comply with existing communication platform (RAS-IRN involvement) to support the MSs Better workload planning to be encouraged, identified safety concerns and public health consequences permitting 48 On-going procedures to date 49 50 50 Prioritised implementation of the pharmacovigilance legislation Regulatory action to safeguard public health 50 Prioritised implementation of the pharmacovigilance legislation by the EMA Communication with stakeholders 51 52 • Agenda is published on Day 1 of PRAC by mid-day • Meeting highlights are published on Friday of PRAC week • Safety referrals are published on Friday of PRAC week • Minutes are published on the following month after adoption Transparency of activities for Pharmacovigilance Risk Assessment Committee Prioritised implementation of the pharmacovigilance legislation by the EMA 53 Communication with stakeholders 54 Prioritised implementation of the pharmacovigilance legislation by the EMA Communication with stakeholders 55 Prioritised implementation of the pharmacovigilance legislation by the EMA Communication with stakeholders 56 Publication of RMP summaries Pilot phase to be initiated in October 2013. • Summary (Part VI.2 of RMP) to be published at the time of the EPAR publication. • Summary to be updated in case of important changes to RMP. • Summary is aligned with other information (EPAR summary, product information). • For all newly - authorised CAPs; • For other (not newly authorised) CAPs, RMP summary to be published when RMP is updated. 57 Prioritised implementation of the pharmacovigilance legislation by the EMA Communication with stakeholders 58 Legal notice: EMA website serves as the EU Medicines Web-portal 59 59 Beyond 2013…what still needs to be done Topics Activities Literature monitoring EMA service to industry for population of EudraVigilance with case reports of old substances. EudraVigilance Delivery of enhanced functionalities and IT system audit results in centralised reporting for industry Article 57(2) data submission and handling Updates (variations) to the data can be submitted by industry and data fully used to support regulation, safety and stakeholder needs. Periodic Safety Update Reports Delivery of PSUR repository and single PSUR assessment process for NAPs allowing centralised reporting for industry and faster warnings for NAPs Risk Management System Implement risk-based system for measuring the effectiveness of risk minimisation Transparency and communication Delivery of EU Medicines web-portal and public hearings. 60 Beyond 2013…what still needs to be done We will get there…..working together Project Coordination Group EMA/MSs Project Team 1 Collection of key information on medicines Revised Project governance model Training Content Group Pharmacovigilance Audit Facilitation Group - EV - ‘e-submission’ activities - Patient reporting EMA/MSs Project Team 2 Better analysis and understanding of data and information - Signal - RMP/PSUR - PASS/PAES - Additional monitoring EMA/MSs Project Team 3 Committees and Communication with stakeholders - Online publishing of information - Coordination of safety messages - Public hearings - Referrals - Transparency/Prod uct information Pharmacovigilance Inspectors Working Group 3. PSUR 5. RMP/PASS/PAES 1. EV/ADR reporting EMA Subproject Teams EMA/MSs Project Teams 4. Additional monitoring 6. Committees 7. Referrals 2. ‘Product info’ (Art 57 /123(4)/Lists Signal Management Review Team (SMART WG) 61 Project Oversight Committee (ERMS-FG) Heads of Medicines Agencies BEMA SG Project Manager WG QM Direct reporting Liaison EMA membership MSs membership EMA/MSs membership What have we achieved A huge change has been delivered for better public health improvement: • Better public participation • increase of patient reports by 10,000 • Patients and HCPs voting on PRAC • Better planning – risk management plans now routine • Better evidence – routine identification of data needs for referrals • Faster decision-making • Referrals finalised in 1 to 8 months • PSURs directly lead to label changes • Greater transparency – agendas, minutes, signals • Better information – black triangle, ADR reporting, warnings 62 But there is still more to do Deliver on the simplifications: • Further improve on the processes already implemented • Centralised ADR reporting • Centralised PSUR reporting • Literature monitoring by EMA for industry Full delivery on better information: • EU medicines webportal Together we can 63 Conclusions Major change has been delivered: • Collaboration • Consultation • Concentration Public health has been improved: • Better evidence • Faster decisions and labelling • Greater transparency • Greater participation and empowerment 64 ��Implementing the pharmacovigilance legislation: focus on EU level activities In this presentation Slide Number 3 Where we are going: legislation objectives Challenges Commission implementing regulation (EU) No 520/2012 Good pharmacoVigilance Practice (GVP) Prioritised implementation agreed by EMA Management Board in December 2011 and 2012 What has been delivered and what is now routine Prioritised implementation of the pharmacovigilance legislation� RMP data RMP Data Slide Number 13 Prioritised implementation of the pharmacovigilance legislation PSURs: Outcomes at PRAC PSURs: Observations Slide Number 17 Slide Number 18 Prioritised implementation of the pharmacovigilance legislation�Collection of key information on medicines � Slide Number 20 Article 57(2) data: business case Article 57(2) data: business case Slide Number 23 Strategy for achieving reliable Article 57(2) data Slide Number 25 Slide Number 26 Extension of the Data Architecture Roadmap to cover other entities Prioritised implementation of the pharmacovigilance legislation �Collection of key information on medicines Spontaneous reporting by patients in EEA Reporting numbers: Pre and Post legislation Prioritised implementation of the pharmacovigilance legislation� Prioritised implementation of the pharmacovigilance legislation�Better analysis/understanding of data and information Achievements of EV Data Quality management 07/2012 – 07/2013 Signals: Data and PRAC Outcomes Signal descriptions – first publication in coming days Prioritised implementation of the pharmacovigilance legislation�Better analysis of data and information Additional monitoring� ‘Black symbol’ for products under additional monitoring (1/2) New communication material on additional monitoring (1/2) Prioritised implementation of the pharmacovigilance legislation Slide Number 41 Prioritised implementation of the pharmacovigilance legislation�Regulatory action to safeguard public health PRAC volumes�(July 2012 – July 2013) Slide Number 44 Slide Number 45 Prioritised implementation of the pharmacovigilance legislation�Regulatory action to safeguard public health Slide Number 47 Slide Number 48 Referrals: Observations On-going procedures to date Prioritised implementation of the pharmacovigilance legislation�Regulatory action to safeguard public health Prioritised implementation of the pharmacovigilance legislation by the EMA�Communication with stakeholders Transparency of activities for Pharmacovigilance Risk Assessment Committee Prioritised implementation of the pharmacovigilance legislation by the EMA Slide Number 55 Prioritised implementation of the pharmacovigilance legislation by the EMA�Communication with stakeholders Prioritised implementation of the pharmacovigilance legislation by the EMA Publication of RMP summaries Prioritised implementation of the pharmacovigilance legislation by the EMA�Communication with stakeholders � Beyond 2013…what still needs to be done Beyond 2013…what still needs to be done Revised Project governance model What have we achieved But there is still more to do Conclusions

Seite 1 von 7 6th Stakeholder Forum 8. November 2012 Am 8. November 2012 fand das sechste Stakeholder Forumtreffen bei der EMA statt. Unter der Leitung von Noël Wathion, EMA, und June Raine, MHRA, diskutierten Vertreter verschiedener Verbandskreise über aktuelle Pharmakovigilanz- Sachverhalte. An der Veranstaltung nahm auch ein Mitarbeiter des BAH in der Delegation der AESGP teil. Einleitend berichteten Mitarbeiter der EMA über den aktuellen Stand der Umsetzung der neuen EU-Pharmakovigilanz-Gesetzgebung. Als wesentliche Fortschritte wurde dargestellt: - Technische Unterstützung der Umsetzung der Pharmakovigilanz-Gesetzgebung durch die EMA (Juni 2011) - Reflection Papers, vor allem die bisher verabschiedeten sieben GVP-Module (I, II, V, VI, VII, VIII und IX) - Im Dezember 2012 sollten folgende Module veröffentlicht werden: III (Inspections), IV (Pharmacovigilance Audits) und XV (Safety Communication) In einer weiteren Welle sollen im 1. und 2. Quartal 2013 veröffentlicht werden: - Modul X (Additional Monitoring) soll erst im 1. oder 2. Quartal 2013 veröffentlich werden, um an die erneut ergänzte neue EU-Gesetzgebung angepasst zu werden - Im 1. Quartal Modul XII (Continuous PV) - Im 2. Quartal soll Modul XI (Public Participation) veröffentlicht werden - Modul XIII (Incident Management) ist in Diskussion; ggf. soll dies in das Modul XII aufgenommen werden. - Modul XIV (International Collaboration) und Modul XVI (Risk-Minimisation Measures) - GVP Product- and Population-specific Considerations – hierzu ist eine ganze Serie von sogenannten P-Dokumenten vorgesehen. - GCP-Annexes: Annex I (Definitions, wurde bereits veröffentlicht und soll in Kürze überarbeitet werden), II (Templates), III (List of other Guidelines) und IV (ICH Guidelines) sind für 2013 geplant. Weiterhin wurden verschiedene Q&A-Dokumente sowie weitere Papiere zur Regelung der Arbeiten in den EMA-Komitees und Business Rules verabschiedet. Darüber hinaus wurden diverse Papiere und andere Unterlagen (u.a. eLearnings) für das xEVMPD erstellt. Die EMA hat jüngst die Webseite überarbeitet; diese soll künftig als EU Medicines Web Portal fungieren und Inhalte zu Safety Referrals und Seite 2 von 7 Komitee-Sitzungen enthalten. Aufgrund der Limitierung der Finanzmittel wurden die verschiedenen Arbeiten einer Prioritätenliste unterstellt. Zuerst sollen Public Health Activities, dann Transparenz- und Kommunikationsangelegenheiten bearbeitet werden. Mit niedrigster Priorität werden Erleichterungen für die Zulassungsinhaber versehen; diese wurde bis auf Weiteres zurückgestellt. RMP-Template: Wurde am 8. November 2012 veröffentlicht und soll ab Januar 2013 verwendet werden. PAES: Arbeiten starteten in Juli 2012, eine Guidance wird in Kürze erwartet. Übermittlung von Produktinformation (Artikel 57 (2): Im Oktober wurde eine erste gemeinsame Arbeitsgruppe zur Planung der weiteren Vorgehensweise eingesetzt. An dieser Arbeitsgruppe ist ein BAH-Mitarbeiter beteiligt. Additional Monitoring: Eine erste Liste von Wirkstoffen soll in März/April 2013 publiziert werden Verbesserte IT Systems: In Bearbeitung Das neue Pharmakovigilanz-Komitee (PRAC) wurde errichtet und arbeitet seit Juli 2012. Tagesordnungen und Protokolle werden laufend publiziert. Die Durchführung von öffentlichen Anhörungen im Zusammenhang mit Referrals wird derzeit beraten. Im Ergebnis sieht sich die EMA auf gutem Weg und innerhalb des gesetzten Zeitplan. Im weiteren Verlauf der Tagung wurden Detailaspekte verschiedener Papiere beraten: GVP Modul III - Pharmacovigilance Inspections Die Ergebnisse der Kommentierungsphase zu diesem GVP-Modul wurden vorgestellt. 17 Organisationen haben Kommentare hierzu eingereicht, darunter nationale und europäische Verbände, Unternehmen und Behörden. Im Ergebnis fielen die Kommentare positiv aus. Diskutiert wurde das Konzept der Supervisory Authority, die sich durch die Lokalisierung des PSMF ergibt, und deren Rolle der Durchführung von Inspektionen vor der Zulassung. Klarstellungen wurden erbeten im Zusammenhang mit der Veröffentlichung von Inspektionsbefunden (non-compliance); hierzu sollen „critical“ und „major findings“ entsprechend der EU-Definition veröffentlicht werden. Weitere Klarstellungen wurden hinsichtlich des PSMF und der mit der Pharmakovigilanz befassten Partnerorganisationen vorgenommen. Weitere Änderungen wurden hinsichtlich der Struktur und der Prozesse des EU-Networks aufgenommen (Minimum-Fristen zur Ankündigung von Inspektionen und deren Tagesordnung, Follow-up und Kommunikation zwischen den Inspektoren und den Bewertern,…). Das überarbeitete Modul soll im Dezember 2012 veröffentlicht werden. Weitergehende Unterlagen zur europäischen Kooperation im Bereich von Pharmakovigilanz-Inspektionen sind in Vorbereitung. In der Diskussion wurde darauf hingewiesen, dass trotz der verbesserten Transparenz von Inspektionsberichten der Schutz vertraulicher Informationen gewährleistet werden muss. Dies wurde zugesagt als Teil der EU-Gesetzgebung. Seite 3 von 7 GVP Modul X - Additional Monitoring of Medicines Ein intensiviertes Monitoring wird aufgrund des begrenzten Informationsbestands nach einer ersten Zulassung eines Produktes für notwendig gehalten. Das neue EU- Additional Monitoring soll obligatorisch für neue Wirkstoffe und biologische Produkte, insbesondere auch Biosimiliars, gelten. Die Liste soll die Bezeichnung und den Wirkstoffnamen von nach dem 1. Januar 2011 in der EU neu zugelassenen Produkten enthalten. Auf Ersuchen einer Nationalen Zulassungsbehörde (NCA) und nach Konsultation des PRAC können weitere Stoffe aufgenommen werden, die mit Einschränkungen zugelassen wurden oder die entsprechende Maßnahmen im RMP auferlegt bekommen haben (bspw. PASS oder PAES). Obligatorisch aufzunehmende Produkte werden automatisch durch die EMA oder die NCAs auf die Liste gesetzt. Die EMA wird zentral zugelassene Produkte binnen 15 Tage nach der Zulassung auf die Liste setzen. Ähnlich sollen die NCAs für optional aufzunehmende Produkte entsprechende Mitteilungen binnen 15 Tagen nach der Zulassung an die EMA richten. Die Produkte bleiben üblicherweise fünf Jahre auf der Liste; eine Streichung erfolgt dann mit der Verlängerung. Für optional auf die Liste aufzunehmende Produkte erfolgt die Streichung nach Erfüllung der Auflagen. Generika sollen ausgenommen werden. Zur Erstellung der Liste wurde am 13. Juli 2012 ein erster Vorschlag mit Kommentierungsfrist bis zum 1. Oktober 2012 veröffentlicht. Hiermit wurde abgefragt, welche Stoffe obligatorisch der Liste unterfallen. In Bezug auf optional aufzunehmende Produkte wurden die NCAs in Bezug auf rein national zugelassene Produkte abgefragt. In Bezug auf MRP/DCP-Produkte wurde untersucht, ob entsprechende Auflagen erteilt wurden. Eine abschließende Auswertung und Veröffentlichung der Liste wurde für Ende des 1. Quartals 2013 angekündigt. Die Liste wird auf der EMA-Webseite publiziert; begleitend soll das zugrunde liegende Konzept der Liste auf der Webseite erläutert werden. Eine Frage zum möglichen Umfang der Liste wurde ausweichend beantwortet. Während die Zahl der obligatorisch aufzunehmenden Stoffe relativ klar sei, bestünden erhebliche Bewertungsunterschiede zwischen den Mitgliedstaaten in Bezug auf zusätzlich aufzunehmende Produkte. Das Modul X selbst wurde im Juni zur Konsultation veröffentlicht. Es ging eine Reihe von Kommentaren ein, die noch ausgewertet werden. Nachgefragt wurde u.a., ob die Gründe für die Aufnahme eines Produkts/Wirkstoffes veröffentlicht werden sollen, worüber noch nachgedacht werden wird. Weiter wurde gefragt, ob parallel auch nationale Systeme (u.a. das brit. black triangle-System) fortgeführt werden sollen, und ob die Unternehmen im Vorfeld der Aufnahme auf die Liste kontaktiert werden. Verschiedenen Kommentatoren erschien die 5-Jahresfrist zu lang. Auch die Methode zur Messung der Effektivität der Maßnahme wurde hinterfragt. Hierzu wurde auf die Methodik zur Bewertung des britischen „black triangle“ verwiesen. Im Ergebnis wurde eingeräumt, dass noch eine Reihe von Fragen aufgeworfen wurde, für die derzeit noch keine befriedigende Antwort gefunden wurde. Auf Nachfrage wurde mitgeteilt, dass alleine die Zahl an Wirkstoffen, die obligatorisch auf der Liste aufzunehmen sind, sicher bei über 100 liegen wird. In Bezug auf die optional aufzunehmenden Stoffe bemühe man sich um eine Seite 4 von 7 europaweit einheitliche und restriktive Interpretation, um die Zahl der Wirkstoffe möglichst niedrig zu halten. Weiterhin wurde bestätigt, dass das schwarze Symbol zwischenzeitlich als auf der Spitze stehendes schwarzes Dreieck identifiziert wurde; dies soll durch Kommissionsentscheidung vor dem Juli 2013 umgesetzt werden. GVP Modul IV – Pharmacovigilance Audit Auch die Behörden müssen sich – ebenso wie die Unternehmen – Audits der Pharmakovigilanz-Systeme unterziehen. Erste Berichte über behördliche Audits sollen bis spätestens zum 21. September 2013 erstellt werden. Die EU-Kommission veröffentlicht diese in Bezug auf die EMA bis zum 2. Januar 2014, in Bezug auf die NCAs ab 21. Juli 2015. Das PRAC soll die Durchführung (Design und Inhalte) der PV Audits überprüfen. Details hierzu sind in Modul IV enthalten. Im Grundsatz wurden die Vorschläge des Moduls von den Verkehrskreisen begrüßt, insbesondere der darin niedergelegte risikobasierte Ansatz. Kommentare in Bezug auf Audits innerhalb der Unternehmen gingen zu folgenden Punkten ein: - Terminologie: Klarstellung von wichtigen Begriffen (u.a. Audit-Strategie, Audit- Programm). Diese sollen durch Fußnoten aufgenommen werden. - Stellung der Auditoren zu Empfehlungen: Die Aufgabe des Auditors zur Übermittlung von Empfehlungen wurde explizit betont. Diese sollen sich an international akzeptierten Audit-Standards orientieren. - Wertigkeit und Kriterien für Audit-Befunde: Diese sollen risikobasiert in critical, major und minor eingestuft werden. Definitionen finden sich im Modul. - Risikobasierter Ansatz in drei Ebenen (strategische, taktische und operationelle Ebene). - Berichtswege: Diese werden durch die Gesetzgebung verlangt und definiert. Berichte sind demzufolge an das obere Management zu richten. - Dokumentation des Audits: Dies wird in den GVP Modulen I und II definiert. - Unabhängigkeit: Die Unabhängigkeit der Auditoren ist gesetzlich gefordert und von zentraler Bedeutung. - Training und Qualifikation des Auditors (siehe Modul I). - Bewertung der Audittätigkeit: Eine Bewertung der Qualität der Arbeit eines Auditors ist eine professionelle Anforderung. - Auditstrategie und -programm: Dies wird in einem Glossar klargestellt. - Detailliertere Empfehlungen zur Durchführung: Weitergehende Empfehlungen wurden verschiedentlich erbeten und sollen aufgenommen werden. Im Ergebnis wurde bestätigt, dass es außerordentlich schwierig ist, generelle Empfehlungen für die heterogene Arzneimittel-Industrie (unterschiedliche Größe, Produktportfolios etc.) zu erarbeiten. Betont wurde ferner, dass die QPPV zwar eine zentrale Rolle im Zusammenhang mit Audits einnimmt, es jedoch nicht erwartet werden kann, dass die QPPV alleine Auditstrategien und -programme ausarbeitet. Dies würde nicht zuletzt deren Unabhängigkeit und die der Auditoren gefährden. Die strategische Planung der Audits soll den Auditoren vorbehalten bleiben. Das finalisierte Modul IV soll am 15. Dezember 2012 veröffentlicht werden. Seite 5 von 7 Weitergehende Empfehlungen sollen, u.a. durch die neu gegründete Pharmacovigilance Audit Facilitation Group, erarbeitet werden. GVP Modul XV - Safety Communication Der Fokus dieses Papiers liegt auf den Prinzipien von „emerging“ Safety Communications, deren Inhalten und Instrumenten sowie der Koordination von entsprechenden Mitteilungen innerhalb der EU. Auch dieses Modul wurde im Juli 2012 als Entwurf zur Kommentierung veröffentlicht. Diverse Organisationen, darunter die Industrieverbände, haben Kommentare eingereicht. Im Ergebnis wurde die Zielsetzung des Papiers klargestellt und Referenzen zu anderen Modulen (v.a. XI und XII) eingefügt. Ferner wird nun empfohlen, eine Kommunikation in beide Richtungen bei der Erarbeitung von entsprechenden Mitteilungen zu etablieren. Im Modul XV werden keine bedeutsamen Änderungen vorgenommen werden, da das Papier bereits breit zwischen den Mitgliedstaaten abgestimmt worden war. Es wurde bestätigt, dass auch bestehende Unsicherheiten bei frühzeitigen Safety-Mitteilungen klargestellt werden sollen; ggf. soll zu einem späteren Zeitpunkt ein follow-up erfolgen. Safety Communications sollen sowohl Verordner als auch klinische Prüfer zu gleicher Zeit adressieren. Für Direct Healthcare Professional Communications (DHPC) sollen spezielle Empfehlungen (besondere Bedeutung dieses Instruments, notwendige Koordination zwischen MAH und Behörden) aufgenommen werden. Schließlich soll eine Referenz auf das EU Medicines Web Portal als einem besonders bedeutsamen Instrument der Kommunikation aufgenommen werden. Darüber hinaus soll der Prozess der Erstellung eines DHPC vereinfacht werden. Es sollen präzisere Anforderungen zur Rolle und Verantwortlichkeit der Beteiligten erstellt werden. Das PRAC soll obligatorisch konsultiert werden. Das Modul soll Ende 2012 finalisiert und veröffentlicht werden. Es wurde mitgeteilt, dass die EU-Kommission den ausstehenden Delegated Act zu Wirksamkeitsstudien ebenso wie den angeforderten Bericht über die Lesbarkeit/Verständlichkeit der Produktinformationen erstellen wird. Auch die neue Gebührenordnung wird die Kommission zu Beginn des kommenden Jahr verabschieden. EURD und PSUR Worksharing-Listen Basis der EURD Liste waren die beiden früheren Worksharing- und Synchronisation- List zur PSUR-Erstellung. Die neue EURD-Liste wird im April 2013 verbindlich. Sinn der Liste ist die Harmonisierung der Data Lock Points (DLP) und der Einreichungsfrequenz von PSURs für Produkte, für die es mehrere Zulassungen gibt. Dies soll die Basis für eine einheitliche Bewertung der PSURs bieten. Die geforderte Periodizität soll auf Basis des Risikoprofils des Wirkstoffs festgelegt werden. Die Daten auf der EURD-Liste ersetzen alle anderen Regelungen und sind von den Zulassungsinhabern binnen sechs Monate nach der Veröffentlichung per Variation zu übernehmen. Nationale Regelungen bleiben nur dann in Kraft, wenn der Wirkstoff nicht in der EURD-Liste enthalten ist. Einer Spalte in der Liste ist zu entnehmen, ob für eigentlich von der PSUR-Erstellung befreite Produkte (u.a. Generika) dennoch ein PSUR erforderlich ist. Seite 6 von 7 Die EURD-Liste soll kontinuierlich gepflegt werden. Für neu zugelassene Wirkstoffe und weitere Produkte können auf Antrag vom Zulassungsinhaber - nach Bestätigung durch die zuständigen Gremien - neue Daten aufgenommen werden. Eingereichte PSURs werden arbeitsteilig von den NCAs bewertet. Mitgliedstaaten haben als Lead Member State auf freiwilliger Basis die PSUR-Bewertung zu einzelnen Wirkstoffen sowie die Durchsicht von Daten in EudraVigilance (u.a. zum Zwecke des Signal Managements) übernommen. Sachstand zum schwarzen Symbol und den neuen Standardtexten Abgestimmte Texte zur Aufnahme von verschiedenen Standardtexten zum „additional monitoring“ und die Aufforderung zur Anzeige von Nebenwirkungen sowie zum schwarzen Symbol (Dreieck) wurden bislang noch nicht publiziert. Die QRD- Gruppe hat unlängst Vorschläge zu den o.g. Punkten vorgelegt, die mit den Verkehrskreisen diskutiert wurden. Die abschließende Beschlussfassung im PRAC erfolgte im Oktober-Meeting, die QRD-Gruppe soll im November erneut beraten. Das CHMP wird voraussichtlich im Dezember den QRD-Vorschlag bestätigen. Im Anschluss erfolgt die Übersetzung der Texte durch den Übersetzungsdienst der EU in alle Amtssprachen. Die Publikation der Texte soll im März oder April 2013 erfolgen. Das schwarze, auf der Spitze stehende Dreieck soll an die Schriftgröße des Textes angepasst werden, jedoch nicht kleiner als 5 mm Seitenlänge. Ein vergleichbares Zeichen wird bereits in Großbritannien und Belgien eingesetzt. Im Gegensatz dazu wird ein schwarzes Dreieck in Finnland und anderen Ländern ebenfalls bereits eingesetzt, allerdings zur Kennzeichnung gekühlt zu lagernder Produkte. Funktionsfähigkeit des PRAC – erste Erfahrungen Das neue Pharmacovigilance Risk Assessment Committee (PRAC) hat im Juli 2012 die frühere Pharmacovigilance Working Party ersetzt. Während die Vertreter der Mitgliedstaaten, der nicht stimmberechtigten Vertreter der EWR-Mitgliedstaaten und einiger Experten planmäßig erfolgte, konnten bislang die Vertreter der Heilberufe und der Patientenorganisationen noch nicht benannt werden. In verschiedenen Dokumenten wurden das Mandat und die Aufgaben des PRAC ebenso wie die Veröffentlichung der Ergebnisse der Tätigkeit und die Spielregeln der Zusammenarbeit mit anderen Gremien der EMA niedergelegt. In Bezug auf Risikomanagement-Pläne wurde das neue Format im Juli 2012 etabliert; es ist verpflichtend ab Januar 2013 (s.o.). Das PRAC soll systematisch Hilfestellungen zu RMPs vor und nach Erteilung der Zulassung geben. In Bezug auf PSURs wurde die zentrale Bewertung durch das PRAC für zentral zugelassene Produkte bereits im Juli 2012 aufgenommen, ebenso wie für PASS und PAES. Das PRAC soll gemeinschaftlich durchgeführte PASS durch die Verbesserung der Prozesse unterstützen. Die erste Liste von Stoffen für das „additional monitoring“ soll auf Vorschlag des PRAC voraussichtlich im März 2013 von der EU-Kommission publiziert werden. Mit dem November-Meeting soll auch das Signal Management durch das PRAC auf Basis einer ersten Liste von 13 bedeutsamen Signalen aufgenommen werden. Erste Referral-Verfahren (Codein, Diclofenac) wurden vom PRAC im Oktober und November aufgenommen. Die EURD-Liste für die PSUR- Erstellung wurde erstellt und bereits einmal ergänzt. Seite 7 von 7 Entscheidungen im PRAC sollen nach Möglichkeit im Konsens getroffen werden; Mehrheitsentscheidungen sind allerdings möglich. Nicht-interventionelle Post-Authorisation (Safety) Studies (PAS/PASS) EMA-Mitarbeiter präsentierten eine Zusammenstellung der gesetzlichen und untergesetzlichen Vorschriften und Empfehlungen zur Planung, Registrierung, Durchführung und Berichtslegung von solchen Studien. U.a. wurde auch auf die Zusammenarbeit mit dem European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCePP) hingewiesen. Nächstes Stakeholder Forum Das 7. EMA Stakeholder Forum zur Pharmakovigilanz ist für den 7. Juni 2013 geplant. Bonn, 8. November 2012 - Kr

5rd Stakeholder Forum 25 May 2012 Noel Wathion/EMA introduced on behalf of Guido Rasi/Executive Director of EMA the 5 th Stakeholder Forum six weeks before new regulation will come into force. He announced that there will be another Stakeholder Meeting by End of June to discuss implementation and maintenance issues regarding the xEVMPD database. Furthermore he notified that the inaugural meeting of the new committee PRAC will take place 19./20. July 2012 in Brussels due to the Olympic Games in London this year. The monthly meeting of PRAC will start in September 2012. Update on Implementation: Pharmacovigilance in EU – where have we come from (June Raine, MHRA) June Raine summarised the history of collaboration in the field of pharmacovigilance since 1995. She focused on the mission of the Pharmacovigilance Working Party and its role within the intensified international cooperation in the EU. Key issues of EU pharmacovigilance is the EudraVigilance database and the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) which covers more the 100 centres all around EU. Another key step in improvement was the concept of work sharing between the National Competent Authorities (e.g., in the area of PSUR assessment) and the inclusion of Patient representatives into the collaboration. To improve transparency and communication the monthly report was established, 30 issues have been published up to now. 52 PhVWP recommendations were published on the HMA website. Update on Implementation: Planning and processes (Peter Arlett, EMA) Presently EMA and Member States are preparing the details of the new business processes, transitional measures and other details like templates, rules of procedures... Regarding 2012 Peter Arlett summarised the status quo of the various topics: - RMPs, PSURs (operation of new procedures for PSURs for CAPs): July 2012 - DSUR implementation: September 2012 - PASS/PAES for CAPs: July 2012 - Article 57: product information already being received - Reporting by patients: cooperation with MS to provide information to patients on direct reporting seems to be on target to agree core data fields for use by MS by July 2012 - EV and signal detection: Operation of revised signal detection process for CAPs in July 2012. The support for the MS to operate new EU signal detection processes for NAPs September 2012. The signal management will start with the PRAC meeting July 2012. Later the maintenance work for the current EV system including data quality needs to be tackled. - Implementation of web-publishing of ADR data: May 2012 (next week) Other issues: - Additional monitoring: development and maintenance of the list of medicines with additional monitoring will be decided at the October meeting of PRAC - IT system to support processing and analysis of data: Reflecting that the finalisation of business requirements for enhanced IT system is still open. A pragmatic use of existing system will be necessary until the new budget will be available. - Scientific committees and decision-making: PRAC will be established July 2012 - Strengthening of referral procedure: July 2012 - Online publishing of information: July 2012 for PRAC outputs - Coordination of safety messages: operation of the coordination of MS´ safety announcements for non-CAPs July 2012 - Public hearings: introduction of public hearing in the context of urgent community procedures. If there will be a referral in autumn then there will be a public meeting. Next steps: 2014: new fees for pharmacovigilance 2015: single assessment processes at full capacity (single assessment procedures for NAP PSURs 2016: enhanced EV system and centralised EMA reporting and new ISO standards in use for adverse reactions and medicinal product reporting Peter reported that more than 30 new or amended major processes and more the 100 new or amended sub-processes were created. Implementing Regulation Florian Schmidt/European Commission presented the status of EC implementing regulation. 29 May 2012 the vote in the Standing Committee on medicinal products for human use, followed by the adoption by the commission in June 2012 is scheduled. It is in discussion to add a transitional phase-in period of six months before the regulation will come into force. Following a questions raised the transitional phase will NOT INCLUDE the pharmacovigilance system master file (PSMF) requirements. Upon personal request it was notified that the European Commission has encouraged the Member States to show some flexibility in case a MAH cannot provide a PSMF within July and August 2012. In addition a delegated act regarding the requirement of Article 10b (post authorisation efficacy studies) European Commission is currently considering possible ways ahead. Later this year a concept paper will be published. Session on Good Vigilance Practice Priya Bahri/EMA presented an overview on the comments received to the recently published seven GVP modules (1 st wave). A 2 nd wave of modules should be published for consultation mid of June covering modules about referrals, inspections, additional monitoring, audits and safety concerns. The 3 rd wave should be launched for public consultation in 3 rd or 4 th quarter 2012; this wave will cover modules on public participation, continuous pharmacovigilance, incident management, international collaboration and on risk minimisation measures. Feedback on questions received – focus on transitional measures Christelle Bouygues/EMA compiled the questions received regarding the “transitional phase” and presented some answers to a number of questions. The Q&A document will cover both CAPs and NAPs as well. The Q&As will discuss various issues: - The Volume 9a will be superseded by the GVP, but it remains applicable till end of transition period. - Pharmacovigilance System Master File, the link to a marketing authorisation, the need for variations (to introduce it, and to change the QPPV data or the location of the PSMF) - Risk Management Plans (when to introduce, format and content) - Requirements for submission of PSMF or RMPs for Herbals and Homeopathics - Post Authorisation Safety Studies (Principles) - PSURs (which procedure, format and content, requirement derogation and the EURD-list) - Product information and black symbol - ADR requirements: EMA prepared a table with the national requirements for ADR submission - Renewal and new requirements The document should be updated frequently; the next update is anticipated in July 2012. It was confirmed that the EURD list should be published in October 2012, and will entering into force April 2013. General update session: Risk management Plans summaries Juan Garcia/EMA gave an update on this topic, with focus on the new proposed EPAR summary, its content and translation. The summary should increase visibility of information on RMPs on website, increase awareness of the concept of risk management, and to improve information on the benefit and risk of each medicine. Next steps will be the final decision on implementation of this concept, to publish a final template and to provide guidance. The PRAC in PRACtice Sheila Kennedy/EMA presented an update regarding the establishment of the new Pharmacovigilance Risk Assessment Committee which will replace the Pharmacovigilance Working Party in July 2012. Regarding the nomination two Member States still outstanding. Liechtenstein has delegated its pharmacovigilance tasks to Austria. EC is in process of selecting their experts; the process should be finalised in the next few weeks. The HCP and patient representatives’ nominations may be facing delays due to European Parliament concerns. The Management Board should be consulted on the final composition of PRAC. There is a high overlap of PRAC members and alternates with existing PhVWP members – 21 Member States and Iceland and Norway having either a future member or alternate currently participating in the PhVWP. The mandate will include the detection, assessment, minimisation and communication relating to the risk of adverse reactions, having due regard to the therapeutic effect of medicinal products, the design and evaluation of PASS, pharmacovigilance audits etc. It shall be responsible for providing recommendations to the CHMP and the CMDh on any questions relating to risks of drugs. The other Committees shall rely on the scientific assessment and the recommendations of the PRAC. The appointment of Rapporteurs should be based on best existing scientific expertise. PRAC Rapporteurs shall closely collaborate with CHMP Rapporteur or RMS for nationally authorised products. The PRAC normally meets at the EMA two weeks before CMDh/CHMP. PRAC meeting occur Monday 1pm to Thursday. The next meetings will take place 19-20 July in Brussels, 3-6 September, 1-4 and 29-31 October and 26-29 November. General update session: Article 57-implementation Ilaria del Seppia/EMA summarised the background, the history and the status of the xEVMPD database. A reduced set of data and the respective guidance documents were provided by 5 th March 2012 as well as the EV WebTrader Application. In the community presently 512 Headquarters and 183 Affiliates are registered. The helpdesk received about 900 questions, the half is still open. Within the test environment by 23 rd of May 78 companies are testing, submitting 1,400 set of data. In the production environment less than 10,000 new products were submitted now. General update session: Additional monitoring and black symbol Mick Foy/MHRA presented the concept to include and to remove a product on resp. from the list. A product will normally remain on the list for five years. In addition to the black symbol products covered shall state on the SmPC and PIL a sentence “This product is subject to additional safety monitoring” and an explanatory statement which need to be adopted by the PRAC (provisionally in September). The list of products will be published on EMA web portal; relevant product should be published on the NCA web portals also. A link to product information and summary RMP need to be provided by the MAH. EMA is responsible for the inclusion of CAPs on the list, and for the automatically removal of products unless there is a recommendation to keep a product on the list. The NCAs are obliged e.g. to inform EMA which mandatory scope products should be included on the list, and to identify optional scope product for PRAC recommendation. The MAH is obliged to include the black symbol and the approved wording on SmPC and PIL, to include information on additional monitoring status in any material distributed to healthcare professionals and patients, and to encourage HCPs and Patients reporting in the SmPC and PIL. The black symbol and wording is matter of consultation starting June 2012. As announced before there will be another Stakeholder Meeting by End of June to discuss implementation and maintenance issues regarding the xEVMPD database. 25.05.2012 - Kr

Die wichtigsten Ergebnisse der vierten Sitzung des Stakeholder Forums zur Umsetzung des EU-Pharmapakets – Teil Pharmakovigilanz ___________________________________________________________________ Am 27. Februar 2012 fand in den Räumen der EMA die inzwischen vierte Sitzung des Stakeholder Forums statt, bei dem regelmäßig über die Fortschritte in der Umsetzung der geänderten EU-Regelungen zur Pharmakovigilanz berichtet wird. Die umfangreiche Agenda des Meetings sah die folgenden Themen vor: - Implementierung der Neuregelungen: Priorisierung der Aktivitäten - EV-Access Policy: Update - PRAC-Nominierung: Update - Übergangsregelungen - Implementierung des Art. 57 (2) Reg 1235/2010 Schwerpunkt bildete allerdings ein Informationsaustausch zum ersten Teil (sieben Module) des Volume 9A-Nachfolgers „Good Pharmacovigilance Practices“ (GVP), die mit Datum vom 20. Februar 2012 zur Kommentierung veröffentlicht wurden. 1. Implementierung und Priorisierung der Aktivitäten Vertreter der EMA fassten den Inhalt des am 2. Februar veröffentlichten Implementierungsplans zusammen (siehe dazu den Bericht im Mitglieder- Rundschreiben Nr. 4/2012 vom 7. Februar 2012). Darüber hinaus wurde klargestellt, dass die zentrale Literaturrecherche durch die EMA ( "Vereinfachung von Prozessen") nur "dritte Priorität" besitzt, nach dem Thema "öffentliche Gesundheit" (erste Priorität) und "Transparenz" (zweite Priorität). Nach Aussage der EMA kann sich der Start dieses "Services" bis zum Jahr 2014 verschieben. Für den Herbst 2012 ist die Veröffentlichung der Liste für das "Additional Monitoring" geplant. Die Veröffentlichung der sogenannten URD-Liste mit Angaben zu Datenstichtagen und Einreichungsfrequenzen von periodischen Sicherheitsberichten zur Kommentierung wurde für April 2012 angekündigt. Eine klare Aussage zu der dringend erwarteten Veröffentlichung der finalen Version der Implementing Measures konnte auch von Seiten der EU-Kommission nicht gemacht werden. Verschoben auf einen "Zeitraum nach 2012" wurde das Single EU Assessment Procedure für PSURs (bzw. PBRERs) sowie die Einrichtung des PSUR-Repository. Demgegenüber soll der Bewertungsprozess für zentral zugelassene Produkte (CAPs) unter Einbindung des PRAC im Juli 2012 starten. Zwei weitere Stakeholder-Meetings sind für das Jahr 2012 geplant. 2. EV-Access Policy: Update Zu diesem Topic wurde über die Aktivitäten (Website-Design, Software- Aktualisierungen etc.) seit dem letzten Meeting berichtet. Zu den Einzelheiten sei auf die entsprechende Präsentation verwiesen. Als nächste Schritte wurden angekündigt: - Stakeholder Testing - Website Performance Testing - Live Website (englisch) voraussichtlich ab dem 20. April 2012 - Live Website (alle EU-Sprachen) voraussichtlich ab dem 1. Juni 2012 3. PRAC-Nominierung: Update Zum grundsätzlichen Nominierungsprozess sei auf die entsprechende Präsentation verwiesen. Zum gegenwärtigen Zeitpunkt sind Nominierungen von 21 Mitgliedstaaten eingegangen, somit stehen Meldungen aus 6 Mitgliedstaaten noch aus. 4. Übergangsregelungen Ein Vertreter der EU-Kommission fasste zusammen, dass grundsätzlich die Neuregelungen für zentral zugelassene Produkte am 2. Juli 2012 und für nationale Zulassungen am 21. Juli 2012 zur Anwendung kommen, allerdings in bestimmten Bereichen eine Übergangsregelung bzw. Umsetzungszeit notwendig sei. Zu den einzelnen Regelungen sei auf die Auflistung in der entsprechenden Präsentation verwiesen. Ein erstes Q&A-Dokument ist inzwischen auf der EMA-Website veröffentlicht worden. Konkrete Übergangsregelungen für PSURs und RMPs sollen in den (finalen) Implementing Measures genannt werden, die, wie oben erwähnt, noch nicht vorliegen. Zur Übermittlungspflicht für nicht schwerwiegende Einzelfallberichte wurde informiert, dass zum gegenwärtigen Zeitpunkt eine große Mehrheit der Mitgliedstaaten sowie die EMA diese in der Übergangszeit nicht fordert. Welche Mitgliedstaaten eine Anforderung angekündigt haben und dies auch aufrecht erhalten wollen, wurde nicht bekannt. 5. Implementierung des Art. 57 (2) Reg 1235/2010 Dr. Sabine Brosch (EMA) fasste den gegenwärtigen Status nochmals zusammen (s. Präsentation). Die aktualisierte Version der "Detailed Guidance" sowie der "Legal Notice" soll in Kürze veröffentlicht werden. Ein Data entry tool soll von der EMA voraussichtlich spätestens ab 15. April 2012 zur eingerichtet werden. 6. Die ersten Module der GVP Mit Datum vom 20. Februar 2012 hat die EMA die ersten sieben Module der „Good Pharmacovigilance Practices“ (GVP) zur Kommentierung veröffentlicht (siehe Bericht an anderer Stelle dieses Rundschreibens). Aufgrund der kurzen Zeit zwischen Veröffentlichung und Meeting sowie des begrenzten Zeitrahmens beim Meeting war nur eine erste Diskussion und ein Informationsaustausch möglich. Generell wurde von Industrieseite die Machbarkeit der beschriebenen sehr umfangreichen Prozesse für kleinere und mittlere Unternehmen angezweifelt. Ebenso wurde die Notwendigkeit von Übergangsregelungen für die Erstellung der neuen periodischen Sicherheitsberichte und Risikomanagement-Pläne (s.o.) betont. Vertreter der EMA fassten in ihren Präsentationen die wesentlichen Inhalte zusammen. Konkrete Kommentierungen zu den sieben Modulen sind bis zum 18. April bei der EMA möglich unter Verwendung der jeweils in den Dokumenten verlinkten Templates, insbesondere auch zu folgenden Themen: - "Social Media" (Modul VI) - Ist von Industrieseite für das PV System Masterfile die Bereitstellung eines Templates gewünscht? - In welchen Bereichen sind zusätzlich zu den in der entsprechenden Präsentation und im Q&A-Dokument genannten Bereichen Übergangsregelungen erforderlich? In diesem Zusammenhang wurde darauf hingewiesen, dass die Veröffentlichung der Module auf der EMA-Website und die verschickten Versionen nicht identisch sind (Zeilenangaben!). Es wird daher dringend darum gebeten, für die Kommentierungen (wegen der Zeilenangabe) die Version auf der EMA-Website zu verwenden. Die Ergebnisnotiz sowie die Präsentationen der einzelnen Referenten des Meetings werden, sobald verfügbar, auf der BAH-Homepage im Mitgliederbereich abrufbar sein unter - Pharmakovigilanz - EU-Vorschlag zur Optimierung der Pharmakovigilanz - Stakeholder Meetings Der BAH wird weiter berichten.

3rd Stakeholder Forum 20 October 2011 Noel Wathion/EMA announced that no additional budget was granted for EMA for the implementation of the new legislation. Due to the budgetary situation, a „fall back‟ scenario was explained. Criteria need to be prioritised for Public health activities, demonstrating increase in transparency, and simplifying processes for the pharmaceutical Industry. In a worst case scenario EMA outlined the work plan to implement a number of new functionalities, and to establish the new committee PRAC in July 2012. The inaugural meeting of the PRAC will take place in Brussels due to the Olympic Games 2012 in London. The monthly meetings of PRAC will start in September 2012 for product related information. Signal detection element will be discussed from July 2012 with the operator union procedure discussions commencing from September 2012. It is hoped that the quality of the EudraVigilance data will continue to be improved. EMA has tendered out the entire quality control to a service provider for the next four years. If additional budget will be granted a lot of more activities could be started by EMA. Due to the limited budget the download function for cases collected in EudraVigilance will not be ready before end of 2012 and it may be phased in two parts. The first phase estimated in January 2012 and by the end of this year it will include MR/DCP and common drug substances. Feedback from the informal Head of Medicines Agencies (HMA) meeting on 5 th October 2011 (Jytte Lyngvig, Head of DKMA) A full day was devoted by the HMA to discuss the issues of implementation of the new pharmaceutical legislation. The objectives are to address strategic issues, to challenge aspects and impact on NCAs and to raise awareness. A number of topics were discussed, e.g. the new PRAC, urgent Union procedures (including the concept of public hearings), the future of PSURs, medicines web portals, coordination of safety announcements (who, when etc.), and pharmacovigilance audits. Regarding the PRAC, the composition (necessary expertise) and the nomination process was discussed, following European Commissions (EC) call for expression of interest for being a member of the PRAC published on 30 th September 2011. Furthermore the procedures including the interaction with CHMP and CMD(h), the definition of PRAC activities, issues related to transparency and communication of Committee´s outcome and the smooth transition between PhVWP and PRAC were a matter of discussion. The PRAC expertise is required to cover areas such as PV and risk assessment expertise, efficacy (benefits) and „clinical‟ practice. Regarding the PSURs, some information was provided on the plans for reaching new legislative proposals such as introducing the new aspect of single EU assessment, legally binding outcome, e- submission to EMA etc. The challenge was to change a running system. The further development depends on the prioritisation of this topic therefore implementation timelines will depend on the prioritisation and it will have an impact on National Competent Authorities (NCAs). Building on existing sites, a European medicines web portal will be launched. The various issues regarding the EU medicines web-portal(s) needed further reflection on many aspects (e.g. multilingualism, IT interoperability). The coordination of safety announcement should ensure that clear messages on medicines safety are provided timely and consistently across EU. There is a need to streamline processes and establish links between EU regulatory network and stakeholders. A balance should be identified for the need of coordinating and the need to meet transparency at the national level. New legislation requires PV system audits of MSs and EMA;the current approach for these audits builds on a system audits to be conducted by each Authority performed by internal auditors. There will be an additional informal HMA meeting in first quarter 2012. Implementation measures Dagmar Stará from the EC presented EC´s concept of the public consultation on the implementing measures for the performance of pharmacovigilance (PV) activities. In general the implementation measures should ensure a unified implementation of the new PV legislation in the EU Member States, and to supplement the essential details of the new PV system, providing technical requirements. EC published a concept paper at 8 September 2011, describing the scope and content of the implementing measures. It was announced that a Stakeholder Meeting should take place 22 November 2011 in Brussels to discuss the concept paper. The document will be updated in the light of the comments and the discussion with the Member States. The goal is to publish the document before the new legislation become operational (July 2012). A question was raised on the status of the delegated act on Post Approval Efficacy Studies (PAES). Bearing in mind that the EC may adopt a delegated act on this topic it was announced that - for the moment - the priorities are focused on the implementing measures Planning for guidance on transitional measures (Christelle Bouygues, EMA) The scope of the “transitional” exercise is to identify changes impacting on the future and ongoing marketing authorisation (MA) application and the existing MAs at the time of entry into force of the new legislation. The ultimate goal is to operate in a consistent and harmonised way to entry into force of the new legislation. Transitional periods are mentioned in different parts of the legislation. Some key changes were identified in a gap analyses (Renewals, Referrals, RMP, Product information, new symbol, PSMF, PASS, PSURs). New requirements: - black symbol in the SmPC and PIL for authorised products subject to additional monitoring - standard texts encouraging healthcare professionals and patients to report ADRs in the SmPC and PIL - PSUR frequency as condition to the MA (even though it‟s a standard cycle) Modification of existing requirements: - Risk Management Plans (RMP - systematic for ALL RMP and summary for MAs authorised after July 2012, new format and content) - PSMF on site and PSMF summary in the MA for products authorised after July 2012. Furthermore there is the introduction of a PSMF summary for authorised products before renewal or July 2015 - Renewal: new submission deadline (from 6 to 9 months before expiry of the MA, updated content of the renewal application) New procedures and decision making process: - Involvement of PRAC (safety related referrals, PSUR, RMP, PASS – conditional to the MA for studies commencing [start of data collection] after July 2012) - New binding decision making process for referrals, PSURs and PASS As a result of the gap analysis there will be a joint activity between EC, EMA and Member States (MS) to publish some guidance in implementing measures and within legal and operational guidance on transitional measures; the papers will be published on EMA website. Some issues which will provide purely interpretation should be published without a prior consultation, other issues will become a matter for public consultation. The key issues should be available before July 2012, but not all. AESGP raised the question if the conditions for non serious case reporting should be addressed in a transitional measure. At the moment there is no clarity which MS will require non-serious cases reporting in the transitional period. It seems that no MS will request such cases; this issue is still open for discussion. The status of the transitional guidance is “network guidance” aiming a more harmonised implementation, but this will not legally binding for the MS. Pharmacovigilance System Master File (Joanna Harper, MHRA) The EU legislation does not contain details on the content and maintenance of the PSMF, therefore an implementing measure should provide these details. This issue was covered in the EC´s concept paper on the implementing measures. Within this concept paper feedback was requested to some topics, such as change control, delegated activities and audit documentation. The information submitted (QPPV contact details, master file location) should be part of the database according Article 57 of the Regulation 726/2004. The MA application should no longer contain the Detailed Description of the Pharmacovigilance System (DDPS). No content of the PSMF should be submitted as part of the MA application. The review of the PSMF is on request at MS discretion. Changes to PSMF content will not require variations as it is not part of MA dossier. Variations (type 1A) are only required to change the items in Article 8 (QPPV and PSMF location). MAHs should be able to fully adopt Master File at the earliest opportunity. Legal and practical proposals are being addressed to enable changes to an existing PV system summary, to facilitate early transition and to realise the efficiencies of not maintaining two systems. The ultimate goal of the PSMF is that PV oversight should be strengthened for both NCAs and QPPV. There was a proposal from BfArM to establish a central database for QPPV contact details to avoid additional variations in the case of change of the QPPV for all products of the company. Regarding national provisions in some Member States this seems to be impossible to implement at the moment. Good Pharmacovigilance Practice (GVP) Priya Bahri/EMA provided an update of the structure and high level principles of the GVP and the EMA/MS technical contribution. GVP should become a self-standing guidance on PV process. The generation of GVP is designated to EMA-Member States Project Teams; the stakeholders expectations should be taken into consideration by internal and public consultation. The documents should become published in two waves. The first wave should be released for public consultation early 2012, and finalised in mid 2012. This wave should cover guidance on the following topics: - I. PV Systems and their quality systems - II. PSMF - V. Risk Management System - VI. ICSRs - VII. PSURs - VIII. PASS - X. Signals. The second wave should cover modules on e.g. audits, inspections, additional monitoring, public participation, communication, continuous PV and regulatory action, referrals / Union procedures and the assessment of effectiveness of PV measures. The second wave should be released for consultation later in 2012, and finalised by end of 2012. The Volume 9a will be replaced by GVP, but there will be a phase of coexistence of both Volume 9a and (approved and draft) GVP chapters. The GVP structure should be modular. The modules will start with an Introduction, followed by a section on Structures and Processes, and a section on Operation of the EU network. There will be some process-specific transparency provisions in each GVP module. For public participation there will be a dedicated GVP module that will state public hearings, patient and healthcare professionals as PRAC Members and ad hoc expert, and the input from Patient and Healthcare Professional Working Parties on risk minimisation and communication. The first public consultation will start February or March next year, with some template for submission of comments and proposals. PRAC The new Pharmacovigilance Risk Assessment Committee will replace the Pharmacovigilance Working Party in July 2012. The mandate will include the detection, assessment, minimisation and communication relating to the risk of adverse reactions, having due regard to the therapeutic effect of medicinal products, the design and evaluation of PASS etc. It shall be responsible for providing recommendations to the CHMP and the CMD on any questions relating to risks of drugs. The other Committees shall rely on the scientific assessment and the recommendations of the PRAC. As mentioned before EC has published a call for expression of interest for being a member of the PRAC published on 30 September 2011. Every Member State could appoint one member and one alternate. Applications for representative of Healthcare Professionals and Patient Organisation should preferably be submitted by the organisations they represent. 6 independent experts should provide PRAC with key expertise for performing its tasks. The members will be appointed for 3-year-term, which may be prolonged once and thereafter renewed. Regarding the workload it is expected to have maximum 4 day meetings within the typical monthly meeting schedule like the other EMA Committees, accompanied with some additional preparatory work. Furthermore PRAC will be supported by electronic meeting tools. It was asked if an industry participation in the PRAC would have been discussed. In the current legal framework there is no industry participation intended, maybe in the context of the next change in the pharmaceutical legislation. Update on the list of Union Reference Dates (URD list) and Frequency of PSUR submission Almath Spooner (IMB) gave an overview on this topic. The URD list will include a comprehensive list of active substances and combinations of actives for which PSURs shall be submitted as determined by the CHMP and PRAC. 4 criteria – on demand by MS, routine standard frequency, condition within MA, substance on the URD list (risk proportionality) – shall be applicable for routine PSUR preparation in the future. It is going to be a step by step implementation. In case of generics, well established use products, homoeopathics and traditional herbals should be in general relieved from routine PSUR preparation. Contrary PSURs (“for cause”) will be necessary, if this is requested by NCA, or if the active is included on the URD list, and the requirement for submission is indicated on the list in accordance with NCAs consultation. The list of substances should be extracted from the EVMPD, from the Work Sharing List or Synchronisation List and from the list of centrally authorised products. The List will aim to be comprehensive. The frequency of submission will be determined based on a risk based approach. It should indicate the situation where MAHs of generics, well established use products, homoeopathics and traditional herbals after PRAC consultation. The list will be dynamic, a change of the URD should be possible, requiring a variation (might be a type 1A). The list will include the substance name, URD, frequency of submission, Data Lock Point (DLP) and the appointed Rapporteur/MS. At the end of the transitional period and following audit, EMA Management Board will announced additional functionalities to submit PSURs to EMA only. A public consultation on the (draft) URD list is foreseen. Implementation of the EV Access Policy (Steven Le Meur/EMA) EMA staff gave an update on enhanced EV functionalities in the context of the new legislation and the concept of the EV access policy. Recently EMA published a guideline on the access policy of Healthcare Professionals and General Public. It was agreed that aggregated data for CAPs (updated on a monthly basis) will be accessible by end of 2011, and aggregated data for all other medicinal products and access to CIOMS-like forms will be granted by end of 2012. Access for MAH, Sponsors and Research Organisations should be granted 2014/2015. The publications will take place in a manner like dashboard. Access should be granted to the reactions (SOC and PT), origin, sex age and some other data fields, and a count of cases. Furthermore a selection of Brand Name or Substance Name should be possible. EMA announced another guidance document to explain the dashboard, appended with a test dashboard (could be used for training purposes). Urgent Union procedures including the concept of public hearings Anthony Humphreys/EMA presented the new procedures for pharmacovigilance driven referrals according the new article 107i of the Directive 2001/83. Art. 107i procedures can be initiated by EC for national authorised products and Member States for centrally authorised Products considering of suspension or revocation of MA, prohibition of supply, refusal of renewal of MA, new contraindication, reduction in the dose, or restriction to the indications; furthermore based on safety concerns from MAH e.g. by interruption of the placing of a product on the market or withdrawn. In case of an initiation of a referral procedure this will be posted at the web portal, accessible by the general public. Within the procedure there is no clock-stop foreseen; the time frame of 60 days for the PRAC and 30 days for the CMD(h) put enormous pressure on the Committees. Public hearings (alternative to written hearings) “may” be performed by PRAC in order to disseminate information (before assessment), to contribute to opinion making (during assessment) or to make decisions transparent and to explain recommendations (at the end). It is up to the MAHs to apply for confidential discussions at PRAC (“right to defence” during procedure). To ensure transparency during the procedure assessment reports will be released. Regarding the appointment of PRAC´s rapporteur and co-rapporteur independence from primary evaluation should be required. There is an open discussion on this and nothing concrete has yet been decided. In the case of urgency temporary measures can implemented at any time, limited to 6 months period (maximum). These can result in a recall from the market, but do not affect the marketing authorisation itself. In the future referrals according to Art. 107i will be initiated in case of PV issues accompanied with urgency. This will be the primary review mechanism for urgent referrals with no rights of re- examination as it will be deemed for urgent action to protect public health. PV issues without urgency will potentially result in a PRAC referral following Article 32 with public hearings and will involve more time invested into evaluating risks. These procedures will start by next year regardless of budgetary implications set out at the beginning by Noel Wathion. Next meeting Provisional dates for the next meetings of the Stakeholder Forum were scheduled on 27 February, 25 May and 1 October 2012. 20.10.2011 Kr

Beschluss des Gemeinsamen Bundesausschusses über eine Änderung der Arzneimittel-Richtlinie (AM-RL): Anlage I - OTC-Übersicht: Nummer 4 (Azidosetherapeutika) und Nummer 36 (Pankreasenzyme) Vom 21. Juni 2012 Der Gemeinsame Bundesausschuss hat in seiner Sitzung am 21. Juni 2012 beschlossen, die Arzneimittel-Richtlinie (AM-RL) in der Fassung vom T. Monat JJJJ „BAnz AT TT.MM.JJJJ V [Veröffentlichungsnummer manuell hinzufügen]“, zuletzt geändert am T. Monat JJJJ „BAnz AT TT.MM.JJJJ V [Veröffentlichungsnummer manuell hinzufügen]“, wie folgt zu ändern: I. Anlage I der Arzneimittel-Richtlinie wird wie folgt geändert: 1. In Nummer 4 wird nach dem Wort „Neoblase“ ein Komma eingefügt und die Wörter „lIeumconduit, Nabelpouch und Implantation der Harnleiter in den Dünndarm“ angefügt. 2. Nummer 36 wird wie folgt neu gefasst: „Pankreasenzyme nur zur Behandlung der chronischen, exokrinen Pankreasinsuffizienz oder Mukoviszidose sowie zur Behandlung der funktionellen Pankreasinsuffizienz nach Gastrektomie bei Vorliegen einer Steatorrhoe.“ II. Die Änderung der Arzneimittel-Richtlinie tritt am Tage nach der Veröffentlichung im Bundesanzeiger in Kraft. Die Tragenden Gründe zu diesem Beschluss werden auf der Internetseite des Gemeinsamen Bundesausschusses unter www.g-ba.de veröffentlicht. Berlin, den 21. Juni 2012 Gemeinsamer Bundesausschuss gemäß § 91 SGB V Der Vorsitzende Hess BAnz AT 10.08.2012 B4

Tragende Gründe zum Beschluss des Gemeinsamen Bundesausschusses über eine Änderung der Arzneimittel-Richtlinie (AM-RL): Anlage I - OTC-Übersicht: Nummer 4 (Azidosetherapeutika) und Nummer 36 (Pankreasenzyme) Vom 21. Juni 2012 Inhalt 1. Rechtsgrundlage .......................................................................................................... 2 2. Eckpunkte der Entscheidung ...................................................................................... 2 3. Verfahrensablauf .......................................................................................................... 3 3.1 Zeitlicher Beratungsverlauf ......................................................................................... 4 4. Dokumentation des gesetzlich vorgeschriebenen Stellungnahmeverfahrens ........ 5 5. Unterlagen des Stellungnahmeverfahrens ................................................................. 7 5.1 Übersicht der eingegangenen Stellungnahmen ........................................................18 2 1. Rechtsgrundlage Nach § 34 Abs. 1 Satz 1 SGB V sind nicht verschreibungspflichtige Arzneimittel von der Versorgung nach § 31 SGB V ausgeschlossen. Der Gemeinsame Bundesausschuss legt gemäß § 34 Abs. 1 Satz 2 SGB V in den Richtlinien nach § 92 Abs. 1 Satz 2 Nr. 6 SGB V fest, welche nicht verschreibungspflichtigen Arzneimittel, die bei der Behandlung schwerwiegender Erkrankungen als Therapiestandard gelten, zur Anwendung bei diesen Erkrankungen mit Begründung vom Vertragsarzt ausnahmsweise verordnet werden können. Dabei ist der therapeutischen Vielfalt Rechnung zu tragen (§ 34 Abs. 1 Satz 3 SGB V). Gemäß § 34 Abs. 1 Satz 5 SGB V gilt der Ausschluss nach Satz 1 nicht für 1. versicherte Kinder bis zum vollendeten 12. Lebensjahr, 2. versicherte Jugendliche bis zum vollendeten 18. Lebensjahr mit Entwicklungsstörungen. Die gesetzlichen Kriterien sind in § 12 Abs. 3 und 4 der gültigen Arzneimittel-Richtlinie wie folgt konkretisiert: § 12 Abs. 3 Eine Krankheit ist schwerwiegend, wenn sie lebensbedrohlich ist oder wenn sie aufgrund der Schwere der durch sie verursachten Gesundheitsstörung die Lebensqualität auf Dauer nachhaltig beeinträchtigt. § 12 Abs. 4 Ein Arzneimittel gilt als Therapiestandard, wenn der therapeutische Nutzen zur Behandlung der schwerwiegenden Erkrankung dem allgemein anerkannten Stand der medizinischen Erkenntnisse entspricht. 2. Eckpunkte der Entscheidung Bei der Geschäftsstelle des Gemeinsamen Bundesausschuss ist am 25. November 2010 das Schreiben einer Fachgesellschaft eingegangen, in dem die Aufnahme der Erkrankungen lIeumconduit, Nabelpouch und Implantation der Harnleiter in den Dünndarm unter der Nummer 4 Azidosetherapeutika sowie die Ergänzung der Gastrektomie unter der Nummer 36 Pankreasenzyme in die OTC-Übersicht angeregt wurde. In der OTC-Übersicht Nummer 4 besteht bereits eine ausnahmsweise Verordnungsfähigkeit von Azidosetherapeutika für die Erkrankung Neoblase. Bei den Krankheiten lIeumconduit, Nabelpouch und Implantation der Harnleiter in den Dünndarm handelt es sich um vergleichbar schwerwiegende Erkrankungen im Sinne der Arzneimittelrichtlinie § 12 Abs. 3. Wie bei der unter Nummer 4 der AM-RL (Azidosetherapeutika) genannten Neoblase verursacht operationstechnisch bedingt enger Kontakt von Urin mit dem Darmepithel auch bei den Erkrankungen lIeumconduit, Nabelpouch und Implantation der Harnleiter in den Dünndarm Störungen des Säure-Base-Haushaltes. Die Verwendung von Azidosetherapeutika entspricht auch bei den vorgenannten Erkrankungen dem allgemeinen Stand der medizinischen Erkenntnisse und gilt als Therapiestandard. Die gültige Nummer 36 der OTC Übersicht sieht bereits eine ausnahmsweise Verordnungsfähigkeit von Pankreasenzymen bei chronisch exokriner Pankreasinsuffizienz und Mukoviszidose vor. 3 Als Folge einer Gastrektomie kann es zu schwerer Steatorrhoe kommen, bedingt durch funktionelle Störung der exokrinen Pankreasfunktion. Dies kann unter spezifischen Voraussetzungen funktionell der chronisch, exokrinen Pankreasinsuffizienz gleichgestellt werden und ist daher einer schwerwiegenden Erkrankung im Sinne des § 12 Abs. 3 der Arzneimittel-Richtlinie vergleichbar. In diesen Fällen entspricht der Einsatz von Pankreasenzymen dem allgemeinen Stand der medizinischen Erkenntnisse und gilt als Therapiestandard. Dementsprechend werden in Anlage I der Arzneimittelrichtlinie die Nummer 4 (Azidosetherapeutika) und die Nummer 36 (Pankreasenzyme) konkretisiert und um die jeweiligen Erkrankungen ergänzt. 3. Verfahrensablauf Mit der Vorbereitung seiner Beschlüsse hat der Unterausschuss „Arzneimittel“ eine Arbeitsgruppe beauftragt, die sich aus den von den Spitzenorganisationen der Leistungserbringer benannten Mitgliedern, der vom GKV-Spitzenverband benannten Mitglieder sowie Vertreter(innen) der Patientenorganisationen zusammensetzt. In der Sitzung am 6. Februar 2012 hat der Unterausschuss „Arzneimittel“ die Einleitung des Stellungnahmeverfahrens zur Änderung der Arzneimittel-Richtlinie, Anlage I (OTC-Übersicht) nach der Überprüfung der tatbestandlichen Voraussetzungen nach § 34 Abs. 1 Satz 2 in Verbindung mit § 12 Abs. 3 und 4 der AM-RL sowie Kapitel 4 § 34 Abs. 1 und 2 Verfahrensordnung (VerfO) für die Erkrankungen lIeumconduit, Nabelpouch und Implantation der Harnleiter in den Dünndarm sowie der Gastrektomie abschließend beraten und nach § 10 Abs. 1, 1. Kapitel der Verfahrensordnung des G-BA die Einleitung eines Stellungnahmeverfahrens einstimmig beschlossen. In Anlage I der Arzneimittel-Richtlinie wird die Regelung in Nummer 4 (Azidosetherapeutike) um die Erkrankungen lIeumconduit, Nabelpouch und Implantation der Harnleiter in den Dünndarm ergänzt. In Anlage I der Arzneimittel-Richtlinie wird die Regelung in Nummer 36 (Pankreasenzyme) wie folgt neu gefasst: „Pankreasenzyme nur zur Behandlung der chronischen, exokrinen Pankreasinsuffizienz oder Mukoviszidose sowie zur Behandlung der funktionellen Pankreasinsuffizienz nach Gastrektomie bei Vorliegen einer Steatorrhoe.“ Es sind keine Stellungnahmen eingegangen. Demzufolge war eine mündliche Anhörung nach § 91 Abs. 9 S. 1 SGB V i. V. m. 1. Kapitel § 12 Abs. 1 VerfO des G-BA nicht durchzuführen. Insofern stellen die vorliegenden tragenden Gründe den aktuellen Stand der zusammenfassenden Dokumentation dar. Der Unterausschuss „Arzneimittel“ hat in seiner Sitzung am 8. Mai 2012 den Beschlussentwurf zur Änderung Anlage I ohne weitere Änderungen konsentiert. Das Plenum hat in seiner Sitzung am 21. Juni 2012 die Änderung der AM-RL in Anlage I beschlossen. 4 3.1 Zeitlicher Beratungsverlauf Sitzung Datum Beratungsgegenstand Sitzung der AG „Nutzenbewertung“ 09.05.2011 Beratung des Schreibens vom 11.11.2010 Sitzung der AG „Nutzenbewertung“ 22.07.2011 Beratung des Schreibens vom 11.11.2010 Sitzung der AG „Nutzenbewertung“ 28.11.2011 Vorbereitung eines Beschlussentwurfs zur Änderung der Arzneimittel-Richtlinie in Anlage I (OTC-Übersicht) Nr. 4 und Nr. 36 47. Sitzung des Unterausschusses „Arzneimittel“ 10.01.2012 Beratung des Beschlussentwurfes über die Änderung Arzneimittel-Richtlinie in Anlage I (OTC-Übersicht) 49. Sitzung des Unterausschusses „Arzneimittel“ 06.02.2012 Beratung des Beschlussentwurfes und Beschlussfassung zur Einleitung eines Stellungnahmeverfahrens zur Änderung Arzneimittel-Richtlinie in Anlage I (OTC- Übersicht) Nr. 4 und Nr. 36 55. Sitzung des Unterausschusses „Arzneimittel“ 08.05.2012 Beratung und Konsentierung des Beschlussentwurfs zur Änderung der Anlage I der AM-RL 51. Sitzung des Plenums 21.06.2012 Beschlussfassung über die Änderung der Anlage I der AM-RL Berlin, den 21. Juni 2012 Gemeinsamer Bundesausschuss gemäß § 91 SGB V Der Vorsitzende Hess 5 4. Dokumentation des gesetzlich vorgeschriebenen Stellungnahmeverfahrens Gemäß § 92 Abs. 3a SGB V ist den Sachverständigen der medizinischen und pharmazeutischen Wissenschaft und Praxis sowie den für die Wahrnehmung der wirtschaftlichen Interessen gebildeten maßgeblichen Spitzenorganisationen der pharmazeutischen Unternehmer, den betroffenen pharmazeutischen Unternehmern, den Berufsvertretungen der Apotheker und den maßgeblichen Dachverbänden der Ärztegesellschaften der besonderen Therapierichtungen auf Bundesebene Gelegenheit zur Stellungnahme zu geben. Folgende Organisationen wurden angeschrieben: Organisation Straße Ort Bundesverband der Pharmazeutischen Industrie e. V. (BPI) Friedrichstr. 148 10117 Berlin Verband Forschender Arzneimittelhersteller e. V. (VFA) Hausvogteiplatz 13 10117 Berlin Deutscher Zentralverein Homöopathischer Ärzte e.V. Am Hofgarten 5 53113 Bonn Bundesverband der Arzneimittel-Importeure e.V. (BAI) EurimPark 8 83416 Saaldorf- Surheim Bundesverband der Arzneimittel-Hersteller e.V. (BAH) Ubierstraße 73 53173 Bonn Deutscher Generikaverband e.V. Kurfürstendamm 190-192 10707 Berlin Gesellschaft für Phytotherapie e.V. Postfach 10 08 88 18055 Rostock Pro Generika e.V. Unter den Linden 32-34 10117 Berlin Gesellschaft Anthroposophischer Ärzte e.V. Roggenstraße 82 70794 Filderstadt Arzneimittelkommission der Deutschen Ärzteschaft (AkdÄ) Herbert-Lewin-Platz 1 10623 Berlin Bundesvereinigung Deutscher Apothekerverbände (ABDA) Deutsches Apothekerhaus Jägerstraße 49/50 10117 Berlin Arzneimittelkommission der Deutschen Zahnärzteschaft (AK-Z) c/o Bundeszahnärztekammer Chausseestr. 13 10115 Berlin Darüberhinaus wurde die Einleitung des Stellungnahmeverfahrens im Bundesanzeiger bekanntgemacht (BAnz. Nr. 44 (S. 1078) vom 16.03.2012). 6 7 5. Unterlagen des Stellungnahmeverfahrens 8 9 10 11 12 13 14 15 16 17 18 5.1 Übersicht der eingegangenen Stellungnahmen Es sind keine Stellungnahmen eingegangen. 1. Rechtsgrundlage 2. Eckpunkte der Entscheidung 3. Verfahrensablauf 3.1 Zeitlicher Beratungsverlauf 4. Dokumentation des gesetzlich vorgeschriebenen Stellungnahmeverfahrens 5. Unterlagen des Stellungnahmeverfahrens 5.1 Übersicht der eingegangenen Stellungnahmen