Arete-Zoe: EU pharmacovigilance legislation

EU PHARMACOVIGILANCE LEGISLATION OVERVIEW OF EUROPEAN PHARMACOVIGILANCE LEGISLATION

AGENDA TIMELINE PHARMACOVIGILANCE STAKEHOLDERS ERMS – RECOMMENDATIONS 2005 – KEY CHANGES 2006 CONSULTATIONS – 2008 PROPOSALS NEW DIRECTIVE 2010/84/EU PHARMACOVIGILANCE NEW REGULATION (EC) NO 726/2004 PHARMACOVIGILANCE OF HUMAN MPS PHARMACOVIGILANCE OF VETERINARY MPS MILESTONES 2011-2012 REGULATION (EU) 520/2012 ICH GUIDELINES GPVP GUIDELINES MILESTONES – FURTHER DEVELOPMENT

TIMELINE Commission Public Consultation: An Assessment of the Community System of PV Announcement by Commission VP Günter Verheugen on strengthening of the EU PV system The EC adopts two legal proposals aimed at amending the EU PV system. PUBLIC CONSULTATION PUBLIC CONSULTATION The European Parliament voted in favor of the EU legislation on pharmacovigilance PUBLIC CONSULTATION Adoption and Publication of Commission Implementing Regulation on PV activities The Commission adopted 4 proposals First black symbols appear 200620072008200920102011201220132014 post-authorization efficacy studies Introducing a Black Symbol Report on human medicines PV tasks of EMA Adoption of a proposal for fees for PV payable to EMA GPvP Guidelines

PHARMACOVIGILANCE STAKEHOLDERS STAKEHOLDERS 2006STAKEHOLDERS 2008 Patients as the users of medicinesPatients as the users of medicines and families and caretakers Doctors, pharmacists, nurses and all other healthcare professionals working with medicines All healthcare professionals but particularly: – doctors, pharmacist, nurses (to advise patients, prescribe medicines, report ADRs) – academia (to conduct safety studies) Regulatory authorities (EMEA, Member States) responsible for monitoring safety of medicines Regulators including Member States National Competent Authorities, EMEA, and the EC Pharmaceutical companies, and companies importing or distributing medicines Healthcare service providers, governments and social insurance schemes Pharmaceutical industry – Marketing Authorization Holders (innovative, generic and over-the-counter) – manufacturers, distributors

PHARMACOVIGILANCE is a key public health function is a process and science of MONITORING the safety of medicines and TAKING ACTION to REDUCE RISKS AND INCREASE BENEFITS from medicines. WHAT IS PHARMACOVIGILANCE? 1. Data collection 2. Data management 3. Signal detection 4. Safety issue assessment 5. Decision-making 6. Communication and action 7. Audit National Competent Authorities EU Agencies PHARMACOVIGILANCE PHASES

EUROPEAN RISK MANAGEMENT STRATEGY RISK MINIMIZATION OTHER ISSUES RISK ASSESSMENT RISK DETECTION TRANSPARENCY STREAMLINING COMMUNICATION STRATEGY CODE of CONDUCT Reporting to EudraVigilance Signal detection and data mining Best evidence concept (2003 ERMS) Innovative Medicines Initiative List of MPs requiring intensive monitoring Network of academic centers to be involved in intensive drug monitoring & other methods “New” PhVWP covering all MP in the EU Optimizing interaction between Committees Strengthening existing peer review systems Improving benefit/risk analysis methodology New concept of RMPs as part of MAs Implementation, remedial action Implementing all other new legal tools Optimizing work-sharing concepts Competence development, resource planning RISK COMMUNICATION 2005 - 2007 ERMS

RECOMMENDATIONS from 2005 Review of the relative contribution of the different sources of safety information needed - ICSRs, PSURs, registries, consumption data, safety studies etc. New legislation strengthens potential impact of tackling safety issues The decision-making process should be reviewed and streamlined The impacts of communications and actions should be checked more systematically The MAHs are primarily responsible for the safety of their products General principles of quality management and continuous quality improvement

2005 KEY LEGISLATIVE CHANGES http://ec.europa.eu/health/files/pharmacovigilance/docs/acs_consultation_final_en.pdf  PV SYSTEM DESCRIPTION and RMS now part of MA application  Provision of PV information by NCAs to stakeholders, patients  Funding of EMA’s PV functions must be public  Clearer legal basis for Eudravigilance  The renewal of MAs will only occur once at 5-years  PSURs 3-yearly rather than 5-yearly  Companies must communicate PV ‘concerns’ first to regulators, then to public  Safety variations to national MAs now form the basis of ‘Community interest’  The legal basis of PV inspections is now explicit  NCAs have the power to vary MAs without company application  For centrally authorized MPs, EMA may request PV data from specific groups  Penalties regulation will provide for Community action for noncompliance  PV SYSTEM DESCRIPTION and RMS now part of MA application  Provision of PV information by NCAs to stakeholders, patients  Funding of EMA’s PV functions must be public  Clearer legal basis for Eudravigilance  The renewal of MAs will only occur once at 5-years  PSURs 3-yearly rather than 5-yearly  Companies must communicate PV ‘concerns’ first to regulators, then to public  Safety variations to national MAs now form the basis of ‘Community interest’  The legal basis of PV inspections is now explicit  NCAs have the power to vary MAs without company application  For centrally authorized MPs, EMA may request PV data from specific groups  Penalties regulation will provide for Community action for noncompliance

2006 CONSULTATIONS CONTRIBUTIONS FROM STAKEHOLDERS Patient, consumer and victim groups (7); Healthcare professional groups (10); Industry including all the relevant European Industry Associations (16); Regulators including EMA Committees and individual medicines agencies (10); WHO UMC and ISoP (48 in total) On 26 February 2007 EC Vice-President Günter Verheugen announced a strengthening of the EU pharmacovigilance system. Better implementation of the current system and proposals to change the legal framework for pharmacovigilance in the EU.

2008 EC LEGAL PROPOSALS 1. THE ISSUE: Improvement of the existing Community legislation on market surveillance of medicines CITIZEN’S SUMMARY 2. WHY SHOULD THE EU BE INVOLVED: To improve the protection of public health in the EC and change the existing PV legislation between 591 and 5910 lives saved per year across the EU saving to society between €237 Million and €2.4 Billion per year 3. PROPOSED ACTIONS: Clear roles and responsibilities for the key responsible parties Rationalizing EU decision-making on drug safety issues Strengthening medicines safety transparency and communication Strengthen companies' PV systems Ensure the proactive and proportionate collection of high quality data Involve stakeholders in PV including ADRs reporting by patients Simplify current PV procedures with efficiency gains for the industry and regulators http://ec.europa.eu/health/files/pharmacos/pharmpack_12_2008/pharmacovigilance/en_summary_phvg_en.pdf

2008 EC LEGAL PROPOSALS Text of the proposal (Directive) Text of the proposal (Regulation) Impact Assessment

2008 EC LEGAL PROPOSALS IMPACT ASSESSMENT: EXECUTIVE SUMMARY Medicines contribute considerably to EU citizens’ health, quality of life, and lifespan. Pharmaceutical market value reached €141 billion in 2006. Adverse drug reactions (ADRs) present a major public health burden in the EU 5% of all hospital admissions are due to an ADR 5% of all hospital patients suffer an ADR ADRs are the 5 th most common cause of hospital death It is estimated that 197,000 deaths per year in the EU are caused by ADRs the total societal cost of ADRs in the EU is €79 billion Medicines contribute considerably to EU citizens’ health, quality of life, and lifespan. Pharmaceutical market value reached €141 billion in 2006. Adverse drug reactions (ADRs) present a major public health burden in the EU 5% of all hospital admissions are due to an ADR 5% of all hospital patients suffer an ADR ADRs are the 5 th most common cause of hospital death It is estimated that 197,000 deaths per year in the EU are caused by ADRs the total societal cost of ADRs in the EU is €79 billion Lack of clear roles, responsibilities and clear obligations (resulting in poor compliance) Slow EU decision-making and frequent disharmony in action taken by the Member States Low levels of transparency and relatively limited EU coordination of communication Cumbersome oversight of companies' pharmacovigilance systems by the authorities; A lack of proactive and proportionate monitoring including PASS Lack of inclusiveness of stakeholders and their virtual absence from decision-making Lack of clear roles, responsibilities and clear obligations (resulting in poor compliance) Slow EU decision-making and frequent disharmony in action taken by the Member States Low levels of transparency and relatively limited EU coordination of communication Cumbersome oversight of companies' pharmacovigilance systems by the authorities; A lack of proactive and proportionate monitoring including PASS Lack of inclusiveness of stakeholders and their virtual absence from decision-making PROBLEM DEFINITION (December 10, 2008) Directive

2008 EC LEGAL PROPOSALS (1)Clear roles and responsibilities for the key responsible parties and obligations (2)Rationalizing EU decision-making and implementation across the community (3)Strengthening medicines safety transparency and communication (4)Strengthen companies' pharmacovigilance systems while reducing administrative burden (5)Ensure the proactive and proportionate collection of high quality data (6)Involve stakeholders in pharmacovigilance including in reporting and decision-making. (1)Clear roles and responsibilities for the key responsible parties and obligations (2)Rationalizing EU decision-making and implementation across the community (3)Strengthening medicines safety transparency and communication (4)Strengthen companies' pharmacovigilance systems while reducing administrative burden (5)Ensure the proactive and proportionate collection of high quality data (6)Involve stakeholders in pharmacovigilance including in reporting and decision-making. (1) No policy-change (2) Deregulation (3) Self-regulation (4) Amendment to the existing European Community legislation (1) No policy-change (2) Deregulation (3) Self-regulation (4) Amendment to the existing European Community legislation This impact assessment has shown that increasing the clarity, efficiency and quality of the EU system of pharmacovigilance presents a win-win situation with major public health improvements of at least 591 lives and €237 Million of public health burden saved per year across the EU and overall cost savings of €145 Million per year to the EU industry sector. OBJECTIVES POLICY OPTIONS CONCLUSION Directive

The Commission services wish to consult stakeholders on the Recommendation on "Pharmacovigilance Urgent Measures" procedure under Article 107 of Directive 2001/83/EC, with a view to the incorporation of the guidance in Volume 9A in Eudralex MILESTONES JAN 2009

“Today's vote is good news for Europeans as the legislation will ensure greater patient safety and improved public health. In addition, by better focusing the work of public administration and industry, red tape shall be cut. Once implemented, the new legislation will strengthen and modernize the current system for monitoring medicinal products for human use in the EU, making it more robust and transparent. Once medicines are authorized and enter the market, they continue to be monitored through the EU system of pharmacovigilance. This is to prevent, detect and assess possible adverse effects. The reporting of adverse drug reactions is essential for effective pharmacovigilance and under the new legislation patients can report adverse drug reactions directly to the competent authorities.” MILESTONES SEP 2010 On September 22, 2010, the European Parliament voted in favor of the EU legislation on pharmacovigilance Statement by John Dalli, European Commissioner for Health and Consumer Policy

DIRECTIVE 2010/84/EU Directive

SCOPE This Directive APPLIES to MPs for human use on EU market This Directive shall NOT apply to: magistral formula, officinal formula, research and development trials, Intermediate products, radionuclides in the form of sealed sources, blood, plasma and advanced therapy MPs This Directive does not affect Rules for the radiation protection for examination or treatment EU Agreement on the Exchange of Therapeutic Substances of Human Origin Member state powers to set of prices and insurance plans National legislation on contraceptives or abortifacients National legislation prohibiting or restricting human or animal cells This Directive does not affect Rules for the radiation protection for examination or treatment EU Agreement on the Exchange of Therapeutic Substances of Human Origin Member state powers to set of prices and insurance plans National legislation on contraceptives or abortifacients National legislation prohibiting or restricting human or animal cells Directive

DEFINITIONS  Medicinal product (MP): Any substance or combination presented as having properties for treating or preventing disease in human beings; or which may be used to restore, correct or modify physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.  Substance: Any matter irrespective of origin which may be human (blood products), animal (micro-organisms, whole animals, parts of organs, secretions, toxins, extracts, blood products), vegetable (micro-organisms, plants, parts of plants, secretions, extracts), chemical (elements, naturally occurring and obtained by chemical change or synthesis)  Immunological medicinal product: Any medicinal product consisting of vaccines, toxins, serums or allergen that produce active immunity, passive immunity, or diagnose the state of immunity. ‘Allergen product’ is intended to identify or induce immunological response.  Advanced therapy MP: Article 2 of Regulation (EC) No 1394/2007  Homeopathic MPs, Radiopharmaceuticals, Blood and plasma products, Herbal medicinal products, Herbal substances, Herbal preparations  Wholesale distribution, Name and common name, immediate and outer packaging Directive

DEFINITIONS  Adverse reaction: A response to a medicinal product which is noxious and unintended.  Serious adverse reaction: An adverse reaction which results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly/birth defect.  Unexpected adverse reaction: An adverse reaction, the nature, severity or outcome of which is not consistent with the summary of product characteristics.  Post-authorization safety study (PASS): Any study relating to an authorized medicinal product conducted with the aim of identifying, characterizing or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures.  Abuse of medicinal products: Persistent or sporadic, intentional excessive use of medicinal products which is accompanied by harmful physical or psychological effects.  Representative of the marketing authorization holder: The person, commonly known as local representative, designated by the MA holder to represent him in a Member State Directive

DEFINITIONS  Risks related to use of the medicinal product: Any risk relating to the quality, safety or efficacy of the MP, patients' health/public health, or environment  Risk-benefit balance: An evaluation of the positive therapeutic effects of the MP in relation to the risks  Risk management system: A set of pharmacovigilance activities and interventions designed to identify, characterize, prevent or minimize risks relating to a MP, including the assessment of the effectiveness of those activities and interventions.  Risk management plan: A detailed description of the risk management system  Pharmacovigilance system: A system used by the MAH and by Member States to fulfil the tasks and responsibilities listed in Title IX and designed to monitor the safety of authorized MP and detect any change to their risk-benefit balance  Pharmacovigilance system master file: A detailed description of the pharmacovigilance system used by the MAH with respect to one or more authorized MPs Directive

PLACING ON THE MARKET Marketing authorization (MA) Application shall be made to the Member State concerned regardless of the procedure Content of MA application: Applicant and manufacturer Name of the medicinal product, constituents, INN, environmental risks Manufacturing method, indications, contra-indications, adverse reactions Posology, pharmaceutical form, method and route of administration, expected shelf life Reasons for any precautionary and safety measures (risks to patients and environment) Control methods employed by the manufacturer Results of pharmaceutical and pre-clinical tests and clinical trials A summary of PV system — QPPV (residence, contact) — signed means statement — location of PSMF — RMP describing RMS Statement that non-EU clinical trials comply with Dir. 2001/20/EC SPC, PIL, packaging Manufacturer authorization; Other MA authorizations /refusals Directive

GENERICS & COMBINATIONS Pre-clinical tests and clinical trials are not required for generics Combinations: results of new pre-clinical tests or new clinical trials relating to that combination shall be provided for the combination but not for each individual substance. For APIs of well-established MP (10 years), with recognized efficacy and safety, appropriate scientific literature is sufficient. Generic medicinal product shall mean a MP which has the same qualitative and quantitative composition and the same pharmaceutical form as the reference MP, and whose bioequivalence has been demonstrated by bioavailability studies. Specific provisions applicable to homeopathic and traditional herbal MPs Directive

SUMMARY OF PRODUCT CHARACTERISTICS 1. Name, strength, pharmaceutical form 2. Qualitative and quantitative composition (common name or chemical description) 3. Pharmaceutical form 4. CLINICAL PARTICULARS therapeutic indications (4.1), posology and method of administration (4.2), contra-indications (4.3), special warnings and precautions for use (4.4), interactions (4.5) use during pregnancy and lactation (4.6) effects on ability to drive and to use machines (4.7) 4.8. undesirable effects, 4.9. overdose (symptoms, emergency procedures, antidotes) 5. PHARMACOLOGICAL PROPERTIES: PD/PK, preclinical safety data 6. pharmaceutical particulars: excipients, major incompatibilities, shelf life, special precautions for storage, nature and contents of container, special precautions for disposal MAH (7), MA numbers (8), renewals (9), text revisions (10) Radiopharmaceuticals: internal radiation dosimetry (11), additional instructions (12) For Article 23 list (EC 726/2004) - black triangle Directive

MARKETING AUTHORIZATIONS MA PROCEDURES MA shall only be examined by 1 NCA, including testing, within 210 days NCAs shall publish MAs together with SPC and PIL + any conditions NCAs shall write an ASSESSMENT REPORT and make it publicly accessible MA PROCEDURES MA shall only be examined by 1 NCA, including testing, within 210 days NCAs shall publish MAs together with SPC and PIL + any conditions NCAs shall write an ASSESSMENT REPORT and make it publicly accessible CONDITIONS WHICH MAY BE PART OF MA Measures for ensuring the safe use to be included in RMS, PASS Stricter ADRs reporting regime, any other conditions or restrictions CONDITIONS WHICH MAY BE PART OF MA Measures for ensuring the safe use to be included in RMS, PASS Stricter ADRs reporting regime, any other conditions or restrictions AFTER APPROVAL NCAs can require the MAH to conduct a PASS/PAES MAH shall inform Member States about the date of actual marketing (cessation) Upon request: volume of sales, prescriptions, data on benefit:risk profile, and PSMF The EC shall adopt arrangements for the examination of variations MAs are valid for 5 years, reevaluation of benefit:risk at renewal, then unlimited AFTER APPROVAL NCAs can require the MAH to conduct a PASS/PAES MAH shall inform Member States about the date of actual marketing (cessation) Upon request: volume of sales, prescriptions, data on benefit:risk profile, and PSMF The EC shall adopt arrangements for the examination of variations MAs are valid for 5 years, reevaluation of benefit:risk at renewal, then unlimited MA REFUSAL Risk-Benefit balance not favorable Therapeutic efficacy unsubstantiated Composition not as declared Particulars do not comply MA REFUSAL Risk-Benefit balance not favorable Therapeutic efficacy unsubstantiated Composition not as declared Particulars do not comply Coordination group shall be set up for the examination of any question relating to MAs authorized by Member States and PV of these MPs Directive

MRP & DCP MA in more than one Member State (Art 28 – 39) -Application based on an identical dossier in all concerned Member States -Reference Member State prepares/updates an assessment report on the MP -Within 90 days the Member States concerned shall approve the assessment report, SPC/PIL, and inform the reference Member State accordingly (Art 28) -The points of disagreement shall be referred to the Coordination group MA in more than one Member State (Art 28 – 39) -Application based on an identical dossier in all concerned Member States -Reference Member State prepares/updates an assessment report on the MP -Within 90 days the Member States concerned shall approve the assessment report, SPC/PIL, and inform the reference Member State accordingly (Art 28) -The points of disagreement shall be referred to the Coordination group  MA granted  MA Subject to certain conditions  MA Suspended  MA Varied  MA Revoked Referrals Member State, Commission, applicant or MAH may refer the matter to CMPH PV related matters shall be referred to PRAC Exceptions for urgent action and emergencies Referrals Member State, Commission, applicant or MAH may refer the matter to CMPH PV related matters shall be referred to PRAC Exceptions for urgent action and emergencies Directive

LABELLING & PACKAGING Particulars that shall appear on MP packaging The package leaflet shall be drawn up in accordance with the SPC The package leaflet must be written and designed to be clear and understandable, clearly legible in the official language or languages of the Member State The package leaflet shall be drawn up in accordance with the SPC The package leaflet must be written and designed to be clear and understandable, clearly legible in the official language or languages of the Member State Name, strength, pharmaceutical form, for whom it is intended, INN/ common nameActive substances per dosage unit and a list of those excipients known to have effectMethod and route of administration a special warnings, expiry, storage precautionsDisposal of unused MPs / waste; name and address of MAH (and representative)Instructions for use (non-Rx)Member States may require also price, reimbursement, legal status Directive

CLASSIFICATION of MPs  NON-RX MEDICINAL PRODUCTS  RX MEDICINAL PRODUCTS MPs on medical prescription for renewable or non- renewable delivery; MPs subject to special & restricted medical prescription SPECIAL MEDICAL PRESCRIPTION: MP containing narcotic or a psychotropic substance MP is likely to present a substantial risk of medicinal abuse/misuse; a precaution RESTRICTED PRESCRIPTION: Pharmaceutical characteristics, novelty, public health, reserved for hospitals use  MEDICINAL PRODUCTS SHALL BE RX IF THEY ARE: Likely to present a danger either directly or indirectly, even when used correctly Are frequently and to a very wide extent used incorrectly Contain substances which require further investigation Are normally prescribed by a doctor to be administered parenterally  NON-RX MEDICINAL PRODUCTS  RX MEDICINAL PRODUCTS MPs on medical prescription for renewable or non- renewable delivery; MPs subject to special & restricted medical prescription SPECIAL MEDICAL PRESCRIPTION: MP containing narcotic or a psychotropic substance MP is likely to present a substantial risk of medicinal abuse/misuse; a precaution RESTRICTED PRESCRIPTION: Pharmaceutical characteristics, novelty, public health, reserved for hospitals use  MEDICINAL PRODUCTS SHALL BE RX IF THEY ARE: Likely to present a danger either directly or indirectly, even when used correctly Are frequently and to a very wide extent used incorrectly Contain substances which require further investigation Are normally prescribed by a doctor to be administered parenterally  Member States shall produce lists of MPs with classifications Directive

MANUFACTURE & IMPORTATION MANUFACTURER & IMPORT All MPs in wholesale distribution & storage have to have MA Notification obligation on imports Authorization for wholesalers Min. requirements for distributors: Premises, installations and equipment, staff, QP All time access to premises Supplies only from authorized suppliers, records of all transactions Emergency plan Subject to authorization Community DB of Authorizations GMP shall be adopted as Directive QP Art 49 at manufacturer’s disposal QP’s responsibilities Art 51: Compliance of each batch Full analysis for all imported batches Mutual recognition of QPs signatures within EU WHOLESALERS Directive

ADVERTISING Advertising of a MP shall encourage their rational use, by presenting it objectively and without exaggerating its properties, not misleading. Member States shall be entitled to ban, on their territory, advertising to the general public of medicinal products the cost of which may be reimbursed. ADVERTISING TO THE GENERAL PUBLIC: BANNED: Rx MP, psychotropic/narcotic OTC MPs and vaccines may be advertised to the general public ADVERTISING TO THE GENERAL PUBLIC: BANNED: Rx MP, psychotropic/narcotic OTC MPs and vaccines may be advertised to the general public — the advertising of MPs to the general public— advertising of MP to persons qualified to prescribe or supply them— visits by medical sales representatives to persons qualified to prescribe MPs— supply of samples, gifts, benefits, bonuses, sponsorship, promotional meetings ‘ADVERTISING OF MPs’ any form of door-to-door information, canvassing activity or inducement designed to promote the prescription, supply, sale or consumption of MPs Member States shall prohibit any advertising of a MPs without MA Directive

INFORMATION & ADVERTISING Member States and other interested parties, present to the European Parliament and the Council a report on current practice with regard to information provision — particularly on the Internet — and its risks and benefits Advertising to the general public of a medicinal product shall:  Clear that the message is an advertisement and that the product is a MP  Include name of the MP, common name, information necessary for correct use of the MP, express, legible invitation to read carefully the instructions on PIL. Any advertising of a medicinal product to HCPs shall include:  Essential information compatible with SPC  The supply classification of the medicinal product Extensive list of DO’s and DON’Ts Member States shall ensure that there are adequate and effective methods to monitor the advertising of medicinal products. Member States and other interested parties, present to the European Parliament and the Council a report on current practice with regard to information provision — particularly on the Internet — and its risks and benefits Advertising to the general public of a medicinal product shall:  Clear that the message is an advertisement and that the product is a MP  Include name of the MP, common name, information necessary for correct use of the MP, express, legible invitation to read carefully the instructions on PIL. Any advertising of a medicinal product to HCPs shall include:  Essential information compatible with SPC  The supply classification of the medicinal product Extensive list of DO’s and DON’Ts Member States shall ensure that there are adequate and effective methods to monitor the advertising of medicinal products. Directive

PHARMACOVIGILANCE TITLE IX PHARMACOVIGILANCE CHAPTER 1 - General provisions (Art 101 to 105)  Member States shall operate a PV system and participate in Union activities  PV system shall collect accurate and verifiable data on ADRs arising from authorized and unauthorized use of the MP and from occupational exposure. Patients, doctors, pharmacists, and other HCPs shall be encouraged to report ADRs  Regular AUDIT of their PV system, results to the EC in 9/2013 and then biyearly  Ensure the public is informed on PV concerns in a timely manner  Take appropriate measures to identify clearly products including batch numbers  Subject noncompliant MAHs to effective, proportionate, dissuasive penalties.  Tasks may be entrusted to another Member State (inform the EC and public)  Member States shall operate a PV system and participate in Union activities  PV system shall collect accurate and verifiable data on ADRs arising from authorized and unauthorized use of the MP and from occupational exposure. Patients, doctors, pharmacists, and other HCPs shall be encouraged to report ADRs  Regular AUDIT of their PV system, results to the EC in 9/2013 and then biyearly  Ensure the public is informed on PV concerns in a timely manner  Take appropriate measures to identify clearly products including batch numbers  Subject noncompliant MAHs to effective, proportionate, dissuasive penalties.  Tasks may be entrusted to another Member State (inform the EC and public) The management of funds intended for activities connected with PV, the operation of communication networks and market surveillance shall be under the permanent control of the NCAs in order to guarantee their independence in the performance of PV activities MEMBER STATES Directive

PHARMACOVIGILANCE  MAH shall operate a PV system equivalent to the relevant Member State’s PV system  Evaluate all information scientifically, consider options for risk minimization and prevention and take appropriate measures as necessary  Regular audit of his PV system, file main findings of the audit on the PSMF until implementation of CAPA  As part of the pharmacovigilance system, the MAH shall Have permanently and continuously at his disposal a QPPV Maintain and make available on request a PSMF Operate a risk management system for each medicinal product; Monitor the outcome of risk minimization measures (RMP, part of MA) Update the risk management system and monitor PV data for new risks TITLE IX PHARMACOVIGILANCE CHAPTER 1 - General provisions (Art 101 to 105) MARKET AUTHORIZATION HOLDER (MAH) Directive

PHARMACOVIGILANCE QPPV Shall reside and operate in the Union (name and contact available to the Agency) Responsible for the establishment and maintenance of the PV system NCAs may require a contact person in addition to QPPV MAs granted before 21 July 2012 do not have RMS for each medicinal product TITLE IX PHARMACOVIGILANCE CHAPTER 1 - General provisions (Art 101 to 105) RMS NCA may impose an obligation on a MAH to operate a RMS for an authorized MP MAH shall have the opportunity to present written observations Based on this response, NCA either confirms or withdraws the obligation RMS confirmed  MA variation to include RMS Directive

PHARMACOVIGILANCE TITLE IX PHARMACOVIGILANCE CHAPTER 2 - Transparency and communications (Art 106) MAH announcements on PV concerns Each NCA shall set up and maintain a web portal and link it to the EMA Member States shall make publicly available at least the following Public assessment reports, together with a summary thereof SPCs and PILs Summaries of RMPs for authorized MPs the list of MPs referred to in Article 23 of Reg 726/2004 Information on the ways of reporting ADRs including the web-forms NCA, Agency, Commission prior to public, agree on a common messageInformation to the public has to be presented objectively and not misleadingMember States, Agency and EC shall inform give each other 24 hrs (unless urgent)Agency coordinates NCAs if active substances are authorized in >1 Member StatePRAC shall advise on these safety announcementsAgency and NCAs shall delete any commercially confidential or personal info Directive

PHARMACOVIGILANCE TITLE IX CHAPTER 3 - Recording, reporting and assessment of pharmacovigilance data (Art 107) SECTION 1 – RECORDING & REPORTING suspected ADVERSE REACTIONS (ADRs)  MAHs shall record all sADRs in the Union or in third countries (spontaneous, PASS)  Those reports are accessible at a single point within the Union  ADRs from clinical trials shall follow Directive 2001/20/EC  MAHs shall not refuse ADRs received by appropriate means from patients and HCPs  MAHs shall submit electronically to EudraVigilance all serious ADRs that occur in the Union and in third countries within 15 days following the Day 0 (first knowledge)  MAH shall submit electronically to Eudravigilance information on all non-serious ADRs that occur in the Union, within 90 days following Day 0.  APIs on the list of publications monitored by the Agency (Art 27), don’t need to report to EV. MAH shall monitor all other literature and report ADRs identified elsewhere.  MAHs shall verify and follow-up ADRs, check for duplicates, and establish SOPs  MAHs shall record all sADRs in the Union or in third countries (spontaneous, PASS)  Those reports are accessible at a single point within the Union  ADRs from clinical trials shall follow Directive 2001/20/EC  MAHs shall not refuse ADRs received by appropriate means from patients and HCPs  MAHs shall submit electronically to EudraVigilance all serious ADRs that occur in the Union and in third countries within 15 days following the Day 0 (first knowledge)  MAH shall submit electronically to Eudravigilance information on all non-serious ADRs that occur in the Union, within 90 days following Day 0.  APIs on the list of publications monitored by the Agency (Art 27), don’t need to report to EV. MAH shall monitor all other literature and report ADRs identified elsewhere.  MAHs shall verify and follow-up ADRs, check for duplicates, and establish SOPs Directive

PHARMACOVIGILANCE TITLE IX CHAPTER 3 - Recording, reporting and assessment of pharmacovigilance data (Art 107) SECTION 1 – RECORDING & REPORTING suspected ADVERSE REACTIONS (sADRs) MS, Agency, and MAHs shall collaborate on detection of duplicates MS report serious ADR within 15 days and NS ADR within 90 days to EudraVigilance These reports shall be accessible to relevant MAHs ADRs from medication errors shall be reported to EudraVigilance and made available to any relevant authorities/organizations within that MS ADRs reported to a different authority shall be forwarded to medical agency of that MS. These reports shall be appropriately identified. MS shall not impose any additional duties on MAHs unless justified. MS, Agency, and MAHs shall collaborate on detection of duplicates MS report serious ADR within 15 days and NS ADR within 90 days to EudraVigilance These reports shall be accessible to relevant MAHs ADRs from medication errors shall be reported to EudraVigilance and made available to any relevant authorities/organizations within that MS ADRs reported to a different authority shall be forwarded to medical agency of that MS. These reports shall be appropriately identified. MS shall not impose any additional duties on MAHs unless justified. Each Member State shall record all ADRs that occur in its territoryPatients and HCP reported ADRs directly to NCA (follow-up by NCA agency)Patients and HCP reported ADRs to MAH  MAH reports to NCA of MS where the ADR occurred (follow-up by MAH) Directive

PHARMACOVIGILANCE TITLE IX CHAPTER 3 - Recording, reporting and assessment of PV data (Art 107) SECTION 2 – PERIODIC SAFETY UPDATE REPORTS PSUR SUBMISSIONS: MA granted after 7/2012: obligation and frequency specified in the MA + upon request MAs granted before 7/2012 Upon request Every 6 months after authorization until launch After launch: 4 x 6 months, 2 x 1 year, every 3 years afterwards HARMONIZATION: MPs with the same API or combination may be amended and harmonized to enable a single assessment to be made in the context of a PSUR work-sharing procedure Union reference date from which the submission dates are calculated MAHs shall electronically submit to the AGENCY PSURs containing: (a) summaries of benefits and risks, including study results (b) scientific evaluation of the risk-benefit balance of the MP (c) volume of sales, volume of prescriptions, estimate of the population exposed  Agency makes PSURs available to NCAs, PRAC, CHMP, and the Coordination group Directive

PHARMACOVIGILANCE TITLE IX CHAPTER 3 - Recording, reporting and assessment of PV data (Art 107) SECTION 2 – PERIODIC SAFETY UPDATE REPORTS REFERENCE DATE CHMP if at least 1 centralized MA for MP the concerned API The coordination group in other cases The first MA in the Union of a MP containing that API or combination MAHs shall submit an application for a variation of the MA accordingly MAHs can ask CHMP or the Coordination group to determine Union reference dates: for reasons relating to public health in order to avoid a duplication of the assessment in order to achieve international harmonization  CHMP & PRAC either approve or reject such requests List of Union reference dates and frequency of submission of PSURs Any change to the dates of submission of PSURs takes effect 6 months publication Directive

PHARMACOVIGILANCE TITLE IX CHAPTER 3 - Recording, reporting and assessment of PV data (Art 107) SECTION 2 – PERIODIC SAFETY UPDATE REPORTS PSUR ASSESSMENTS NCAs shall assess PSURs for new/changed risks A single assessment of PSURs shall be performed by either a Member State appointed by the Coordination group or a rapporteur appointed by PRAC Assessment report shall be prepared within 60 days  Agency and MS  Agency shall send the report to the MAH  MS and MAH have 30 days to comment  15 days for update  PRAC  issue a recommendation  Action (maintain, vary, suspend or revoke the MA)  MAH submits variations Assessment reports of the requested PSURs shall be communicated to PRAC PRAC shall consider need for a single assessment report for all MAs for the same API PSUR ASSESSMENTS NCAs shall assess PSURs for new/changed risks A single assessment of PSURs shall be performed by either a Member State appointed by the Coordination group or a rapporteur appointed by PRAC Assessment report shall be prepared within 60 days  Agency and MS  Agency shall send the report to the MAH  MS and MAH have 30 days to comment  15 days for update  PRAC  issue a recommendation  Action (maintain, vary, suspend or revoke the MA)  MAH submits variations Assessment reports of the requested PSURs shall be communicated to PRAC PRAC shall consider need for a single assessment report for all MAs for the same API Based on opinion of CHMP the Committee shall (a) adopt a decision concerning the measures to be taken in respect of MAs (b) adopt a decision to vary, suspend or revoke the MAs Directive

PHARMACOVIGILANCE The AGENCY The Agency, NCAs and MAH shall inform each other about new/changed risks MAHs shall inform the Agency and NCAs about new/changed risks TITLE IX CHAPTER 3 - Recording, reporting and assessment of PV data (Art 107) SECTION 3 – SIGNAL DETECTION NCAs & the AGENCY Monitor the outcome of risk minimization measures contained in RMPs Assess updates to the RMS Monitor the data in EudraVigilance for new/changed and risk-benefit balance PRAC Initial analysis and prioritization of signals of new/changed risks Assessment of those signals and agreement on any subsequent action Directive

PHARMACOVIGILANCE PRAC may hold public hearings; issues recommendation within 60 days  no further evaluation or action is required at Union level  the MAH should conduct further evaluation together with the follow-up of the results  the MAH should sponsor a PASS and follow up the results  the Member States or MAH should implement risk minimization measures  the MA should be suspended, revoked, not renewed, or varied  SPC/PIL changes TITLE IX CHAPTER 3 - Recording, reporting and assessment of PV data (Art 107) SECTION 4 – URGENT UNION PROCEDURE Urgent action is considered necessary, if the Member State considers  Suspending or revoking a MA  Prohibiting the supply of a MP  Refusing the renewal of a MA  New contraindication, a reduction in dose, or a restriction to the indications  If the MAH that interrupted sales or has taken action to have a MA withdrawn MEMBER STATE or the COMMISSION Inform the other Member States, the Agency and the Commission On the basis of the opinion of the CHMP the Commission shall adopt a decision All Assessments shall be made public Directive

PHARMACOVIGILANCE TITLE IX CHAPTER 4 - NON-INTERVENTIONAL POST-AUTHORIZATION SAFETY STUDIES The study may commence only after endorsement from NCA or PRAC Substantial amendments to protocol: to PRAC or NCA MAH shall evaluate impact on benefit:risk profile  PRAC may make recommendations  MAH submits MA variation Directive Initiated, managed or financed by the MAH, voluntarily or obligatoryNI-PASS involve the collection of safety data from patients or HCPsNot to be used as a marketing tool, payments to HCPs restricted (time and expenses)Final report to the NCA where the study was conducted within 12 monthsMAH shall monitor and assess the data for the risk-benefit balanceMAH shall submit a draft protocol to PRAC (or the MS which requested the study) PRAC shall decide within 60 days  Endorse the protocol  Object (marketing purpose, design not appropriate to fulfil the study objectives, or within scope of Directive 2001/20/EC)

PHARMACOVIGILANCE TITLE IX CHAPTER 5 - IMPLEMENTATION, DELEGATION AND GUIDANCE (Art 108) The Commission shall make public a report on the performance of PV tasks by the Member States on 21 July 2015 at the latest and then every 3 years thereafter Directive

PHARMACOVIGILANCE TITLE X – SPECIAL PROVISIONS ON MPs DERIVED FROM HUMAN BLOOD AND PLASMA (Art 109-110) Collection and testing of human blood and human plasma: Directive 2002/98/EC amending Directive 2001/83/EC applies Standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components Member States shall take the necessary measures to promote Community self-sufficiency in human blood or human plasma, and encourage the voluntary unpaid donation of blood and plasma and shall take the necessary measures to develop the production and use of products derived from human blood or human plasma coming from voluntary unpaid donations. Directive

PHARMACOVIGILANCE TITLE XI – SUPERVISION AND SANCTIONS (Art 111-110) NCA shall report on whether the inspected entity complies with GMP, GDP, and Title IX Member State, the Commission or the Agency may conduct inspection in third countries Within 90 days of an inspection a certificate of GMP shall be issued to a manufacturer Member States shall enter the certificates of GMP in a Community database NCA shall report on whether the inspected entity complies with GMP, GDP, and Title IX Member State, the Commission or the Agency may conduct inspection in third countries Within 90 days of an inspection a certificate of GMP shall be issued to a manufacturer Member States shall enter the certificates of GMP in a Community database NCAs and the Agency, ensure compliance with legal requirements governing MPs, by means of inspections and laboratory tests Member States and the Agency shall cooperate on inspections in third countries NCAs and the Agency, ensure compliance with legal requirements governing MPs, by means of inspections and laboratory tests Member States and the Agency shall cooperate on inspections in third countries Such inspections shall be carried out by the competent authority empowered to: Inspect the manufacturing or commercial establishments of manufacturers of MPs or APIs, and laboratories employed MAH to carry out checks pursuant to Article 20 Take samples for independent tests (OMCL, national labs)OMCL Examine any documents relating to the object of the inspection, Inspect the premises, records, documents and PSMF of the MAH and its contractors Such inspections shall be carried out by the competent authority empowered to: Inspect the manufacturing or commercial establishments of manufacturers of MPs or APIs, and laboratories employed MAH to carry out checks pursuant to Article 20 Take samples for independent tests (OMCL, national labs)OMCL Examine any documents relating to the object of the inspection, Inspect the premises, records, documents and PSMF of the MAH and its contractors Directive

PHARMACOVIGILANCE TITLE XI – SUPERVISION AND SANCTIONS (Art 111-119) Pharmacovigilance inspections If the outcome of the inspection is non-compliance with PSMF/Title IX:  Deficiencies to MAH and give him the opportunity to submit comments.  Member State concerned informs other MS, Agency and the Commission  Effective, proportionate and dissuasive penalties for MAHs. Pharmacovigilance inspections If the outcome of the inspection is non-compliance with PSMF/Title IX:  Deficiencies to MAH and give him the opportunity to submit comments.  Member State concerned informs other MS, Agency and the Commission  Effective, proportionate and dissuasive penalties for MAHs. TITLE XII – STANDING COMMITTEE The Commission shall adopt any changes which are necessary in order to adapt Annex I to take account of scientific and technical progress. The Commission shall be assisted by the Standing Committee on Medicinal Products for Human Use in the task of adapting to technical progress. Where it considers it necessary in the interests of public health, a Member State may require the MAH to submit samples of each batch for testing (live vaccines, immunological MP, new/altered technology, blood/plasma) MA shall be suspended, revoked or varied if the MP is harmful, lacks therapeutic efficacy, risk-benefit balance is not favorable, composition is not as declared, or particulars supporting the application are incorrect. Where it considers it necessary in the interests of public health, a Member State may require the MAH to submit samples of each batch for testing (live vaccines, immunological MP, new/altered technology, blood/plasma) MA shall be suspended, revoked or varied if the MP is harmful, lacks therapeutic efficacy, risk-benefit balance is not favorable, composition is not as declared, or particulars supporting the application are incorrect. Directive

PHARMACOVIGILANCE NCAs shall communicate to each other relevant information Conclusions reached in line with Art 111(1) shall be valid throughout the Community WHO shall be informed on actions which may affect public health in third countries The Agency shall publish annually a list of the MPs for which MAs have been refused, revoked or suspended, prohibited supply, or withdrawn from the market. The Commission shall set up a publicly accessible register of authorized MPs and make this register available on their website. Member States shall ensure that appropriate collection systems are in place for medicinal products that are unused or have expired. TITLE XIII – GENERAL PROVISIONS (Art 122-127) Directive

PHARMACOVIGILANCE ANNEX I - ANALYTICAL, PHARMACOTOXICOLOGICAL AND CLINICAL STANDARDS AND PROTOCOLS IN RESPECT OF THE TESTING OF MEDICINAL PRODUCTS Part I - STANDARDISED MARKETING AUTHORISATION DOSSIER REQUIREMENTS Describes the application format, SPC, PIL, labelling, leaflet and presentation requirements for standard applications (Modules 1 to 5). Part II - SPECIFIC MARKETING AUTHORISATION DOSSIERS AND REQUIREMENTS provides derogation for ‘Specific applications’, i.e. well established medicinal use, essentially similar products, fixed combinations, similar biological products, exceptional circumstances and mixed applications (part bibliographic and part own studies). Part III - PARTICULAR MEDICINAL PRODUCTS deals with ‘Particular application requirements’ for biological medicinal products (Plasma Master File; Vaccine Antigen Master File), radio-pharmaceuticals, homeopathic medicinal products, herbal medicinal products and orphan medicinal products. Part IV - ADVANCED THERAPY MEDICINAL PRODUCTS deals with ‘Advanced therapy medicinal products’ and concerns specific requirements for gene therapy MPs (using human autologous or allogeneic system, or xenogeneic system) and cell therapy MPs both of human or animal origin and xenogeneic transplantation MPs. Directive

NEW REGULATION (EC) No 726/2004 Reg 726/2004

NEW REGULATION (EC) No 726/2004 Centralized procedure Compulsory: High-tech MPs – biotech: gene therapy, cell therapies, xenogenic somatic therapy Orphan drugs, entirely new active substances Therapeutic indication: AIDS, cancer, neurodegenerative disorders, diabetes auto-immune diseases and other immune dysfunctions and viral diseases (2015) Optional: Added value for the patient or society – therapeutically innovative, OTC Veterinary products: prophylactic measures for epizootic diseases, new API Applications made directly to the EMA  EU MA granted by the Commission Centralized procedure Compulsory: High-tech MPs – biotech: gene therapy, cell therapies, xenogenic somatic therapy Orphan drugs, entirely new active substances Therapeutic indication: AIDS, cancer, neurodegenerative disorders, diabetes auto-immune diseases and other immune dysfunctions and viral diseases (2015) Optional: Added value for the patient or society – therapeutically innovative, OTC Veterinary products: prophylactic measures for epizootic diseases, new API Applications made directly to the EMA  EU MA granted by the Commission Decentralized procedure Introduced in 2004, applicable to majority of conventional MPs. Through this procedure an application for the MA of a MP is submitted simultaneously in several Member States, one of them being chosen as the "Reference Member State". At the end of the procedure national marketing authorizations are granted in the reference and in the concerned Member States. Decentralized procedure Introduced in 2004, applicable to majority of conventional MPs. Through this procedure an application for the MA of a MP is submitted simultaneously in several Member States, one of them being chosen as the "Reference Member State". At the end of the procedure national marketing authorizations are granted in the reference and in the concerned Member States. Mutual recognition procedure Applicable to the majority of conventional MPs, is based on the principle of recognition of an already existing national marketing authorization by one or more Member States. Mutual recognition procedure Applicable to the majority of conventional MPs, is based on the principle of recognition of an already existing national marketing authorization by one or more Member States. Reg 726/2004

NEW REGULATION (EC) No 726/2004 Reg 726/2004  Applications for the MA described above shall be submitted to the Agency  The Community shall grant and supervise MAs for human MP according to Title II  The Community shall grant and supervise MAs for veterinary MP according to Title III PURPOSE: Community procedures for the authorization, supervision and PV of MPs for human and veterinary use, and to establish EMA (the Agency) Member States are free to choose which MPs will be covered by their social security No MP appearing in the Annex may be placed on the Community market w/o MA Any MP not appearing in the Annex may be granted a MA if: the MP contains a new active substance the MP constitutes a significant innovation, or that it is in the interests of patients Immunological veterinary MPs for the treatment of diseases subject to EC measures A generic MP under some circumstances After the consultation with competent committee of the Agency the Commission may adapt the Annex to technical and scientific progress without extending the scope

NEW REGULATION (EC) No 726/2004 Submission and examination of applications for MAs  CHMP: opinions on centralized MAs, and PV  PRAC: scientific assessment of PV tasks and RMS  The Committee: Decision, resolution of disagreements, inspections  The draft decision shall be forwarded to Member States and the applicant for comments  The Agency may impose obligations on MAH such as RMS, PASS or PAES after MA, any obligations shall be part of MA  Information about all refusals and the reasons for them shall be publicly accessible  Authorized MPs shall be entered in the Community Register of MPs and given a number  The European Public Assessment Report (EPAR) shall include a summary for the public  MA may be renewed after 5 years, once renewed it shall be valid indefinitely  products of major interest may receive accelerated assessment procedure TITLE II - AUTHORISATION AND SUPERVISION OF MEDICINAL PRODUCTS FOR HUMAN USE (Art 5 to 15) Reg 726/2004

NEW REGULATION (EC) No 726/2004 Reg 726/2004 TITLE II – Chapter 2 – Supervision and penalties (Art 16 to 20) MAH shall inform the Agency and the Commission of any prohibition/restriction imposed by the NCAs and any other information which affects benefits and risks The MAH shall ensure that the product information is kept up to dateThe Agency may at any time ask MAH to forward data on risk-benefit balance For MPs imported from third countries, the supervisory authorities for imports shall be the NCA that granted the authorization A Member State may request assistance from another MS or from the Agency.Supervisory authority for PV shall be the NCA of the MS where PSMF is locatedSupervisory authorities for PV are responsible for verifying MAH PV compliance The Commission may, following a request from a Member State or the Committee, or on its own initiative, require a third country manufacturer to submit to an inspection

NEW REGULATION (EC) No 726/2004 Reg 726/2004 TITLE II – Chapter 3 – PHARMACOVIGILANCE (Art 21 to 29) RISK MANAGEMENT SYSTEM The Agency may impose an obligation on a MAH to operate a RMS and submit detailed description of the RMS for the MP concerned (30 days for MAH to respond)  The Commission shall withdraw or confirm the obligation The Agency maintains and publishes list of MPs that are subject to additional monitoring List shall include link to the product information and to the summary of RMP SPC and PIL shall include black symbol and statement ‘This medicinal product is subject to additional monitoring’ RISK MANAGEMENT SYSTEM The Agency may impose an obligation on a MAH to operate a RMS and submit detailed description of the RMS for the MP concerned (30 days for MAH to respond)  The Commission shall withdraw or confirm the obligation The Agency maintains and publishes list of MPs that are subject to additional monitoring List shall include link to the product information and to the summary of RMP SPC and PIL shall include black symbol and statement ‘This medicinal product is subject to additional monitoring’ URGENT ACTION: Member State may suspend the use of a MP in its territory MS initiative  inform the Commission and the Agency in 1 working day  Agency informs other MS, MS inform their HCPs through professional associations URGENT ACTION: Member State may suspend the use of a MP in its territory MS initiative  inform the Commission and the Agency in 1 working day  Agency informs other MS, MS inform their HCPs through professional associations

NEW REGULATION (EC) No 726/2004 TITLE II – Chapter 3 – PHARMACOVIGILANCE (Art 21 to 29) EUDRAVIGILANCE DATABASE The Agency shall set up and maintain ‘Eudravigilance database’ Clinical Trial Module (EVCTM) for reporting of SUSARs - Directive 2001/20/EC Post-Authorisation Module (EVPM) for ICSRs – Reg.726/2004, Dir. 2001/83/EC MPs within the terms of the MA, off-label, PASS and occupational exposure Annual report on the Eudravigilance was released in April 2014 Annual report on the Eudravigilance The Agency shall announce when Eudravigilance has achieved full functionality Shall be fully accessible to NCAs, Agency and the Commission, and partially to MAHs Appropriate level of access to other stakeholders, aggregated data to the public Reg 726/2004

NEW REGULATION (EC) No 726/2004 Reg 726/2004 TITLE II – Chapter 3 – PHARMACOVIGILANCE (Art 21 to 29) Individual ADRs and follow-ups Submitted by MAH shall be transmitted electronically upon receipt to the NCA of the Member State where the reaction occurred The Agency shall develop web-based forms for ADR reporting by HCPs and patients http://www.adrreports.eu/ Some key changes from August 2014: Addition of the Uppsala Monitoring Centre of the WHO as a new stakeholder group who will be provided weekly with ICSRs originating from within the EEA Enhanced access of MAHs to reports on their MPs to support their signal detection and other PV obligations Access to more detailed ICSR data for researchers in response to justified research requests Addition of international medicines RAs as a new stakeholder group, which can obtain ad-hoc data Increased emphasis on confidentiality of personal data to protect the identity of patients and reporters of ADRs

REGULATION (EC) No 726/2004 TITLE II – Chapter 3 – PHARMACOVIGILANCE (Art 21 to 29) Repository for PSURs The Agency shall maintain a repository for PSURs and assessment reports eCTD submission compulsory since March 2014 Repository expected to be available in January 2015 Reg 726/2004

NEW REGULATION (EC) No 726/2004 TITLE II – Chapter 3 – PHARMACOVIGILANCE (Art 21 to 29) The Agency shall, maintain web-portal on MPs authorized in the EU  The names of members of the Committees and the members of the Coordination group, together with their professional qualifications and declarations  Agendas and minutes from each meeting of the Committees on PV activities  A summary of the RMPs for authorized MPs  The list of MPs referred to in Article 23  List of the locations in the Union where PSMF is kept and contact for PV enquiries for all MPs authorized in the Union;  Information about how to report ADRs for patients and HCPs, including links  Union reference dates and frequency of submission of PSURs  Protocols and public abstracts of results of PASS  Conclusions of assessments, recommendations, opinions, approvals and decisions taken by the Committees and by the coordination group, the NCAs and the Commission  Before the launch of this portal, and during subsequent reviews, the Agency shall consult relevant stakeholders, including patient and consumer groups, HCPs and industry The Agency shall, maintain web-portal on MPs authorized in the EU  The names of members of the Committees and the members of the Coordination group, together with their professional qualifications and declarations  Agendas and minutes from each meeting of the Committees on PV activities  A summary of the RMPs for authorized MPs  The list of MPs referred to in Article 23  List of the locations in the Union where PSMF is kept and contact for PV enquiries for all MPs authorized in the Union;  Information about how to report ADRs for patients and HCPs, including links  Union reference dates and frequency of submission of PSURs  Protocols and public abstracts of results of PASS  Conclusions of assessments, recommendations, opinions, approvals and decisions taken by the Committees and by the coordination group, the NCAs and the Commission  Before the launch of this portal, and during subsequent reviews, the Agency shall consult relevant stakeholders, including patient and consumer groups, HCPs and industry Reg 726/2004

NEW REGULATION (EC) No 726/2004 Reg 726/2004 TITLE II – Chapter 3 – PHARMACOVIGILANCE (Art 21 to 29) The Agency monitors selected medical literature for ADRs to MPs containing certain APIs List of APIs and journals monitored by the Agency Draft guidance for monitoring of biomedical literature The Agency shall enter ADRs into Eudravigilance Submissions of PSURs laid down in the Directive PSUR assessment shall be conducted by rapporteurs appointed by PRAC and CHMP or the Reference Member State for the MP concerned  Draft Assessment report (60 days)  Agency and PRAC  The Agency sends the report to the MAH  MAH and PRAC may submit comments (30 days) to the Agency and the rapporteur  The rapporteur updates the Assessment report (15 days) and forward it to PRAC  PRAC shall adopt the assessment and issue recommendation on MA  CHMP adopts an opinion: maintenance, variation, suspension, revocation (30 days) The final recommendations, opinions and decisions shall be made public The Agency monitors selected medical literature for ADRs to MPs containing certain APIs List of APIs and journals monitored by the Agency Draft guidance for monitoring of biomedical literature The Agency shall enter ADRs into Eudravigilance Submissions of PSURs laid down in the Directive PSUR assessment shall be conducted by rapporteurs appointed by PRAC and CHMP or the Reference Member State for the MP concerned  Draft Assessment report (60 days)  Agency and PRAC  The Agency sends the report to the MAH  MAH and PRAC may submit comments (30 days) to the Agency and the rapporteur  The rapporteur updates the Assessment report (15 days) and forward it to PRAC  PRAC shall adopt the assessment and issue recommendation on MA  CHMP adopts an opinion: maintenance, variation, suspension, revocation (30 days) The final recommendations, opinions and decisions shall be made public

NEW REGULATION (EC) No 726/2004 Reg 726/2004 TITLE II – Chapter 3 – PHARMACOVIGILANCE (Art 21 to 29) The Agency shall perform regular independent audits of its PV tasks The Commission shall make public a report on the performance of PV tasks by the Agency The Agency shall perform regular independent audits of its PV tasks The Commission shall make public a report on the performance of PV tasks by the Agency Measures the Agency shall can take: Monitor the outcome of risk minimization measures contained in RMPs Assess updates to the RMS Monitor the data in Eudravigilance for new and changed risks Measures the Agency shall can take: Monitor the outcome of risk minimization measures contained in RMPs Assess updates to the RMS Monitor the data in Eudravigilance for new and changed risks PRAC shall perform the initial analysis and prioritization of signals  The assessment of those signals and agreement on any subsequent action shall be conducted in a timescale commensurate with the extent and seriousness of the issue. PRAC shall perform the initial analysis and prioritization of signals  The assessment of those signals and agreement on any subsequent action shall be conducted in a timescale commensurate with the extent and seriousness of the issue. The Agency, NCAs, and MAH shall inform each other on new risks For NI-PASS concerning MP for human use Art 107 of Directive 2001/83/EC shall apply The Agency shall collaborate with the WHO in PV matters that affect third countries The Agency and the European Monitoring Centre for Drugs and Drug Addiction shall exchange information on the abuse of MPs and information related to illicit drugs The Agency and Member States collaborate on harmonization and standardization of PV The Agency, NCAs, and MAH shall inform each other on new risks For NI-PASS concerning MP for human use Art 107 of Directive 2001/83/EC shall apply The Agency shall collaborate with the WHO in PV matters that affect third countries The Agency and the European Monitoring Centre for Drugs and Drug Addiction shall exchange information on the abuse of MPs and information related to illicit drugs The Agency and Member States collaborate on harmonization and standardization of PV

NEW REGULATION (EC) No 726/2004 Reg 726/2004 TITLE III – AUTHORISATION AND SUPERVISION OF VETERINARY MEDICINAL PRODUCTS (Art 30 to 40) APPROVAL: CVMP opinion VMP for food-producing animals: statement of the max. residue level Reg. EEC 2377/90 Conditions or restrictions regarding safe & effective use and supply or use of the VMP Draft text of the labelling and package leaflet proposed by the The assessment report  The Commission prepares decision  Member States and the Applicant CVMP established, responsible for opinion on authorizations of veterinary products Each application for MA of a VMP shall include all particulars and a fee Special provisions fro GMO-containing products Opinion on application of the Committee shall be given within 210 days Evaluation of the application by CVMP corresponds with CHMP In case of negative response the applicant may ask for re-examination The Agency forwards the final opinion of the CVMP to the Commission, to Member States and to the applicant, together with assessment supporting its conclusions

NEW REGULATION (EC) No 726/2004 Reg 726/2004 TITLE III – AUTHORISATION AND SUPERVISION OF VETERINARY MEDICINAL PRODUCTS (Art 30 to 40) MA shall be refused if Quality, safety or efficacy of the VMP insufficiently demonstrated Performance enhancers: animal safety and welfare/consumer safety not considered Residues are a health hazard for the consumer VMP for use prohibited under other Community provisions Particulars or documents provided by the applicant are incorrect Labelling and package leaflets not in accordance with Title V of Directive 2001/82/EC The refusal of a Community MA prohibits the placing on the market throughout the EC The Standing Committee for VMP: The opinion of the said Standing Committee is to be given in writing Member States send observations on the draft decision to the Commission (22 days) Important new questions of a scientific or technical nature  back to the Agency

NEW REGULATION (EC) No 726/2004 Reg 726/2004 TITLE III – AUTHORISATION AND SUPERVISION OF VETERINARY MEDICINAL PRODUCTS (Art 30 to 40) Authorized VMPs  Number in the Community Register which shall appear on the packaging  Notification of MAs shall be published in the Official Journal of the European Union  The Agency shall immediately publish the assessment report on the VMP  The European Public Assessment Report (EPAR) shall include a summary for the public  MAH shall inform the Agency of the dates of actual placing on the market  MA shall be valid for 5 years, then re-evaluation  VMP not present on the market for 3 consecutive years loses MA  Accelerated assessment procedure if there is a major public/animal health interest The granting of authorization shall not affect the civil or criminal liability of the manufacturer or the MAH pursuant to the applicable national law in Member States

NEW REGULATION (EC) No 726/2004 TITLE III – AUTHORIZATION AND SUPERVISION OF VETERINARY MEDICINAL PRODUCTS (Art 41 to 45) SUPERVISION AND SANCTIONS After an authorization variations may be required to update scientific methods NCAs / Agency may require samples for testing MAH shall provide technical expertise for detecting residues of VMP MAH shall inform the Agency, Commission and Member States of any prohibitions VMPs manufactured in the EC: The supervisory authorities is the NCA which granted the MA VMPs imported from third countries: The supervisory authority is the NCA which granted authorization to the importer The Commission may require a third country manufacturer to submit to an inspection Suspension of VMP to protect human or animal health or the environment Member State or at the Commission's request HCPs shall be rapidly informed through professional associations Reg 726/2004

NEW REGULATION (EC) No 726/2004 Reg 726/2004 TITLE III – PHARMACOVIGILANCE OF VETERINARY MEDICINAL PRODUCTS QPPV Shall reside in EC Responsible for establishing and managing PV system which ensures that all ADRs which are reported to the company is recorded, collected, evaluated and collated Access at a single point within the EC Preparing the reports for NCAs and the Agency and responding to their requests ADRs ADRs of VMPs authorized in the EC  EMA 15-day reports: All suspected SUSARs All adverse human reactions Transmission of infectious agent via a VMP occurring in a third country Animal owners and breeders shall communicate any ADRs to HCPs or NCAs MAH and NCAs report all ADRs to EMA CVMP: publishes opinions on measures (Art 46 to 54) PSUR submissions 6 months until placing on the market 4x6m, 2x1yr, then every 3 years PSURs: Scientific evaluation, risk- benefit balance PV concerns to Agency first, then public Member States enforce PV obligations The Agency can requests data on specific groups (first 5 years) The Agency cooperates on veterinary PV with international organizations VOLUME 9 B Detailed guidance

NEW REGULATION (EC) No 726/2004 Reg 726/2004 TITLE IV – THE EUROPEAN MEDICINES AGENCY — RESPONSIBILITIES & ADMINISTRATIVE STRUCTURE Tasks of the Agency (Art 55 to 66) Management Board Responsibilities set out in Articles 65, 66 and 67 EMA (The Agency) Coordinates scientific resources provided by Member States for the evaluation, supervision and pharmacovigilance of MPs  Establish standing and temporary working parties and scientific advisory groups  Appoint members from the lists of experts and consult them PRAC Recommendations to CHMP and the Coordination group on PV & RMS CVMP Prepares opinions of the Agency on evaluation of VMPs Pediatric Committee CHMP Prepares opinions of the Agency on evaluation of MPs Committee on Herbal Medicinal Products Committee on Orphan Medicinal Products Committee for Advanced Therapies Executive Director Responsibilities set out in Article 64 Secretariat Technical, scientific and administrative support for the Committees

NEW REGULATION (EC) No 726/2004 Reg 726/2004 TITLE IV – THE EUROPEAN MEDICINES AGENCY — RESPONSIBILITIES & ADMINISTRATIVE STRUCTURE Coordination of the scientific evaluation MPsEMA web-portal: status of MPs, publication of assessment reports, SPCs/PILsCreating a database on MPs, to be accessible to the general publicCoordinating the monitoring of MPs to ensure safe use, incl. parallel distributionEnsuring the collation and dissemination of information on ADRs via EudraVigilanceAssisting Member States with the rapid communication of PV concernsAdvising on residue limits of VMPs and biocides; ATB use in food-producing animalsCoordinating compliance verification with GMP, GLP, GCP, GPvPProviding technical and scientific support to improve international cooperationAdvising on the conduct of the tests and trials on quality, safety and efficacy of MPsDossiers on potential biological warfare pathogens and countermeasuresCoordination of the supervision of the quality of MPs (OMCL or national labs)Forwarding annually to the budgetary authority any relevant information TASKS OF THE AGENCY (Art 55 to 66)

NEW REGULATION (EC) No 726/2004 Reg 726/2004 TITLE IV – THE EUROPEAN MEDICINES AGENCY — RESPONSIBILITIES & ADMINISTRATIVE STRUCTURE Tasks of the Agency (Art 55 to 66) The Agency may give an opinion on MPs intended exclusively for third countriesThe Agency shall identify potential scientific conflicts and seek consensusThe Agency can question NCAs methods of determination of therapeutic value of MPsEach Member State appoint 1 member to CHMP and CVMP for a three-year termThe committees may co-opt up to five additional membersThe members of each Committee may be accompanied by other expertsThe Executive Director of the Agency can attend all meetings of the committeesExecutive Director of the AgencyEach NCA shall monitor the scientific level and independence of the evaluationsEach committee shall establish its own rules of procedure TASKS OF THE AGENCY (Art 55 to 66)

NEW REGULATION (EC) No 726/2004 Reg 726/2004 TITLE IV – THE EUROPEAN MEDICINES AGENCY — RESPONSIBILITIES & ADMINISTRATIVE STRUCTURE SPCs and PILs of authorized MPs, reference to clinical trials First Centrally authorized MPs, later to include all MPs on the market in the Community Public format for submissions since 2011, MAH submissions by 2 July 2012

NEW REGULATION (EC) No 726/2004 Reg 726/2004 TITLE IV – THE EUROPEAN MEDICINES AGENCY RESPONSIBILITIES & ADMINISTRATIVE STRUCTURE Tasks of the Agency The Agency shall keep an up-to-date list of accredited experts The performance of scientific services may result in a call for an expression of interest Members of the Board, committees, rapporteurs and experts shall not industry ties Pharmacovigilance Risk Assessment Committee (PRAC) 1 member / 1 alternate member appointed by each Member State (can be delegated) 6 members appointed by the Commission (public call for expressions of interest) 1 member / 1 alternate member appointed by the Commission (to represent HCPs) 1 member / 1 alternate member appointed by the Commission (patient organizations) PRAC Mandate All aspects of the risk management of the use of MPs including the detection, assessment, minimization and communication relating to the risk of ADRs Assessment of the design and evaluation of PASS Pharmacovigilance audit (Art 55 to 66)

NEW REGULATION (EC) No 726/2004 Reg 726/2004 TITLE IV – THE EUROPEAN MEDICINES AGENCY — RESPONSIBILITIES & ADMINISTRATIVE STRUCTURE Tasks of the Agency (Art 55 to 66) The Executive Director Is the legal representative of the Agency Responsibilities: Day-to-day administration of the Agency Managing all the Agency resources Ensuring that the time-limits are complied with by the Agency Ensuring appropriate coordination between the Committees Preparation of the estimates of the Agency's revenue and expenditure All staff matters Providing the secretariat for the Management Board Yearly report on the Agency activities and work program to the Management Board Guido Rasi

NEW REGULATION (EC) No 726/2004 TITLE IV – THE EUROPEAN MEDICINES AGENCY — RESPONSIBILITIES & ADMINISTRATIVE STRUCTURE Tasks of the Agency (Art 55 to 66) The Management Board Representatives: Member States (1 of each), Commission (2), European Parliament (2), patients' organizations (2), doctors' organizations (1), veterinarians (1) – 3 year term Appointed by the Council in consultation with the EP from Commission’s list Adopts its rules of procedure and elects Chairman (3 year term) Decisions of the Management Board shall be adopted by 2/3 majority Invites the chairmen of the scientific committees to attend  Adopts an opinion on procedures of the CHMP and CVMP, adopts procedures for the performance of scientific services  Appoints the Executive Director  Approves Agency’s annual work program  EP, Council, Commission, Member States  Adopts Agency’s annual report and forwards it to the EP, the Council, the Commission, the EESC, the Court of Auditors and Member States (15 June each year)EESC  Adopt the budget of the Agency and internal financial and staff regulation provisions  Develops contacts with stakeholders  Adopts provisions for providing assistance to pharmaceutical companies  Adopts rules to ensure the availability of information to the public Reg 726/2004

NEW REGULATION (EC) No 726/2004 Reg 726/2004 TITLE IV – THE EUROPEAN MEDICINES AGENCY — RESPONSIBILITIES AND ADMINISTRATIVE STRUCTURE Estimates of all the revenue and expenditure shall be part of the Agency’s budget Revenue: contribution from the Union and fees paid PV-related activities, operation of communications networks, and market surveillance are controlled by the Management Board to guarantee independence of the Agency Expenditure: staff remuneration, administrative and infrastructure costs, and operating expenses as well as expenses resulting from contracts with third parties Estimate of revenue and expenditure goes to the Commission (draft EU budget) The Executive Director implements the Agency’s budget The Agency’s budget shall comply with the general Financial Regulation The final accounts shall be published The Agency shall accede to the Interinstitutional Agreement (1999) concerning internal investigations by the European Anti-Fraud Office (OLAF) The structure and the level of the fees Article 67(3) shall be established by the Council The Commission shall adopt provisions for small and medium-sized enterprises Financial Provisions (Art 67 to 70)

NEW REGULATION (EC) No 726/2004 Reg 726/2004 TITLE IV – THE EUROPEAN MEDICINES AGENCY — RESPONSIBILITIES AND ADMINISTRATIVE STRUCTURE The Agency shall have legal personality Jurisdiction: The Court of Justice of the European Communities Non-contractual liability: the Agency shall make good any damage caused by it or by its servants in the performance of their duties. The personal liability of its servants towards the Agency shall be governed by the relevant rules applying to the staff of the Agency Regulation (EC) No 1049/2001 regarding public access to European Parliament, Council and Commission documents shall apply to documents held by the Agency The Protocol on the Privileges and Immunities of the European Communities applies The Commission may invite representatives of international organisations with an interest in the harmonisation of regulations to participate as observers The Management Board ensures availability of non-confidential regulatory, scientific or technical information on authorization or supervision of MPs The internal rules and procedures of the Agency, its committees and its working groups shall be made available to the public at the Agency and on the Internet. General Provisions governing the Agency (Art 71 to 80)

NEW REGULATION (EC) No 726/2004 Reg 726/2004 TITLE V – GENERAL AND FINAL PROVISIONS (Art 81 to 86) Making a MP belonging to the categories referred to in Article 3(1-2) 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 can not be treated satisfactorily by an authorized MP The MP must either subject of an application for a MA or in clinical trials Member State notify the Agency on occasions of compassionate use Civil or criminal liability of the manufacturer or of the applicant is not affected The Commission may impose financial penalties on MAHs. The maximum amounts, conditions and methods shall be laid down by the Commission The Commission shall publish the names of the MAHs involved and the amounts of and reasons for the financial penalties imposed Compassionate use

8 September – 7 November 2011 Public consultation on a concept paper on implementing measures for PV activities Regulation (EU) No 1235/2010 and Directive 2010/84/EU adopted harmonizing measures Description of implementing measures can be found in the concept paperconcept paper MILESTONES 9 February 2012: Responses to the Public consultationResponses to the Public consultation Quality systems for PV activities by MAHs, NCAs, and the Agency Transparency, meeting records of PV sessions and committees should be public instantly. NCAs should be asked to report back to HCPs/patients on the follow-up to ADRs Calls for risk-based approach rather than a full audit every two years. Concerns over long document retention periods Suggestions to simplify requirements for generics and herbal products PSMF Welcomed as a concept, concerns over duplication of paper available elsewhere Suggestions to concentrate on system description, keep modular content with annexes Location: electronic, linked to place where QPPV operates Concern over notifications on substantial changes, introduction of logbook with changes

MILESTONES 2012 FebMarAprMayJunJulAugSep 18-Jun-2012: Consultation on Introduction of Fees for PV to be charged by EMAConsultation on Introduction of Fees for PV to be charged by EMA The new PV legislation enables the Agency to charge fees for its new PV activities. Directorate General seeks feedback from all stakeholders on the proposed structure and levels of fees for pharmacovigilance. 20-Jun-2012: Adoption of Commission Implementing Regulation on PV activitiesAdoption of Commission Implementing Regulation on PV activities 20-Jun-2012: Regulation (EU) 520/2012 on the performance of PV activities published in the Official Journal of the European Union. This Implementing Regulation complements the 2010 PV legislation, which starts to apply in July 2012, by providing more technical details.Regulation (EU) 520/2012 25-Jun-2012: Guidelines on Good Pharmacovigilance PracticesGuidelines on Good Pharmacovigilance Practices 20-Feb-2012: Q&A on transitional arrangements on the new PV provisions in July 2012Q&A on transitional arrangements on the new PV provisions in July 2012 10-Feb-2012: PHARMACOVIGILANCE: Proposal for a Directive & RegulationProposal for a Directive Regulation INFORMATION ON MPs TO THE GENERAL PUBLIC: Proposal for a Directive & RegulationProposal for a Directive Regulation

9 February 2012: Responses to the Public consultationResponses to the Public consultation MILESTONES Terminology, format and content Need for flexibility in terminology for specific products (homeopathics) or for patients Lack of clarity of definitions of off-label, abuse, misuse and medication error Processing of personal data and standardized pseudonymisation has been suggested. Provision of literature references, summaries in English and translation issues. PSURs and RMPs A need for alignment with the ICH draft E2C (R2) has been highlighted Signature of QPPV on all PSURs perceived as administrative burden transparency of RMPs, publication of summary or full RMP Signal detection and risk identification Requests for further clarification of roles of the Agency, NCAs and MAHs Need for multidisciplinary approach to signal detection supported by statistical analysis Clarification of identified risk, validated signal and threshold for transmission to the PRAC To mitigate risk associated with the concentration of all tasks in 1 Member State, well- documented decision-making, transparency and a peer review system have been proposed.

REGULATION (EU) 520/2012 PHARMACOVIGILANCE SYSTEM MASTER FILE QPPV – responsibilities, authority, CV, Eudravigilance registration, contact, backup Contact person at national level – responsibilities Organizational structure of the MAH, list of sites where individual PV tasks take place Description of location, functionality & operational responsibility for computer systems Data handling and recording process for PV tasks, record management system System for monitoring the performance of the PV system Subcontracted parts of the PV system List of MPs, list of SOPs, tasks delegated by QPPV List of all scheduled and completed audits, logbook, performance indicators List of other PSMFs held by the same MAH ANNEX MAH shall keep the PSMF up to date, deviations shall be documented until resolved MAH shall notify the Agency of change in the location of the PSMF and name of QPPV PMSF may be stored in electronic form, printed copy needed for audits and inspections Logbook: any alteration of the PSMF (NCA/Agency may request copy) Subcontracting: MAH remains fully responsible for PSMF Location: where the main PV activities are performed or where QPPV operates QPPV has permanent access to the PSMF, available for inspections Regulation (EU) 520/2012

REGULATION (EU) 520/2012 Regulation (EU) 520/2012 Compliance management Continuous monitoring and evaluation of PV data for new/changed risks, and for quality, integrity and completeness of the information Effective communication on new/changed risks, update of product information Requirements for the quality systems (QS) for the performance of PV activities MAHs, NCAs, and the Agency shall establish a QS QS: organizational structure, responsibilities, procedures, processes and resources, resource management, compliance management and record management QS: Planning, Adherence, QC/QA, and Improvements Written policies and procedures: quality plans, quality manuals and quality records Performance indicators for PV activities Minimum requirements for MAHs HR: Sufficient competent and appropriately qualified and trained personnel QPPV has to have access to a medic and sufficient authority The duties of the managerial and supervisory staff shall be defined in job descriptions Hierarchical relationships shall be defined in an organizational chart Training plans and records available for audit or inspection

REGULATION (EU) 520/2012 Regulation (EU) 520/2012 Record management and data retention All PV information shall be handled in accordance with record management system MAHs shall establish mechanisms enabling the traceability and follow-up of ADRs Records to be kept 5 years after termination of PSMF Retention of PV data: end of authorization + 10 yrs Audit Risk-based shall be performed regularly, results to be reported to the management Corrective action(s), including a follow-up audit shall be taken where necessary Minimum requirements for NCAs and the Agency Competent and qualified staff and keep training plans and records for audits The organizational structures and the distribution of responsibilities shall be clear Establish specific procedures and processes for PV tasks Ensure independence of assessments and effective and for conducting inspections The Agency shall establish procedures for the monitoring of medical literature Record management system to ensure retrievability and traceability Retention of PV data: termination of the system + 5yrs, expiration of MA+10 yrs

REGULATION (EU) 520/2012 Minimum requirements on Eudravigilance MAHs, NCAs and the Agency shall cooperate in monitoring of the data in EV ‘SIGNAL’ is information arising from one or multiple sources, potentially causal association, or a new aspect of a known association, either adverse or beneficial, of sufficient likelihood to justify verificatory action. Only adverse signals shall be considered for EV Identification of changed risks and new risks (MP or API) PRAC may publish a list of events that need to be considered Methodology for determining the evidentiary value of a signal Relevance, strength, consistency, exposure–response, biological plausibility, etc. PRAC shall regularly review the methodology(ies) used and publish recommendations Signal management process Signal detection Signal validation Signal confirmation Signal analysis and prioritization Signal assessment Recommendation for action Regulation (EU) 520/2012

REGULATION (EU) 520/2012 Regulation (EU) 520/2012 Signal detection support The Agency shall support the monitoring of the Eudravigilance by providing NCAs: Data outputs and statistical reports for review of all ADRs Customized queries supporting the evaluation of ICSRs and case series Customized grouping and stratification of data enabling identification of high risk groups Statistical signal detection methods The Agency shall also ensure appropriate support to MAHs Signal detection audit trail NCAs and the Agency shall keep an audit trail of their signal detection activities The audit trail shall show how signals have been detected, validated and assessed Worksharing for signal management The Agency shall publish a list of APIs that are subject to work sharing and the lead Member State and co-leader appointed for monitoring those substances in the Eudravigilance

REGULATION (EU) 520/2012 Regulation (EU) 520/2012 EN ISO 11239:2012 ISO/FDIS 11239:2012 EN ISO 11240:2012 ISO/FDIS 11240:2012 Use of terminology, formats and standards The lists of Standard Terms published by the European Pharmacopoeia Commission Medical Dictionary for Regulatory Activities (MedDRA) as developed by the ICH(M1)MedDRA EN ISO 11238:2012 ISO/FDIS 11238:2012 EN ISO 11239:2012 ISO/FDIS 11239:2012 EN ISO 11240:2012 ISO/FDIS 11240:2012 EN ISO 11615:2012 ISO/FDIS 11615:2012 EN ISO 11616:2012 ISO/FDIS 11616:2012 EN ISO 11238:2012 ISO/FDIS 11238:2012 EN ISO 27953-2:2011 ISO 27953-2:2011 EN ISO 11615:2012 ISO/FDIS 11615:2012 EN ISO 11616:2012 ISO/FDIS 11616:2012 ICH M2 Electronic Standards ICH E2B(R3) Electronic Transmission of ICSRs Extended Eudravigilance Medicinal Product Report Message (XEVPRM)

REGULATION (EU) 520/2012 Regulation (EU) 520/2012 Transmission of reports of suspected ADRs ICSRs - Suspected ADRs to a MP that occur in a single patient at a specific point in time Content: reporter, patient, ADR, MP MAHs and NCAs shall document follow-up ICSRs: all available information Literature: reference ‘Vancouver style’, comprehensive summary, full English translation Study: study type, name and number for studies not covered by Directive 2001/20/EC Reporter (contact, residence, qualifications), Patient (medical history, concurrent conditions), MPs (product info, concomitant medication), ADR including outcome, case narrative for serious ADRs, reasons for nullifying or amending the report Follow-up procedure shall be in place to obtain batch number (traceability) Original narrative shall be provided together with English summary Member States may report narratives in their official language and translate per request

REGULATION (EU) 520/2012 Regulation (EU) 520/2012 RISK MANAGEMENT PLANS Content Identification or characterization of the safety profile of the MP concerned Indication of how to characterize further its safety profile Measures to prevent or minimize risks associated with its use Post-authorization obligations as a condition of the marketing authorization Several products with the same API may be subject to the same RMP PASS initiated, managed or financed by MAH (voluntary/obligatory) Summary of the RMP Publicly available summary shall include key elements with focus on risk minimization and important information on potential and identified risks and missing information Separate summary of the RMP for each MP Updates Updated RMP (or updated modules) has to be submitted to the NCAs or the Agency as Each submission shall have a distinct version number and shall be dated Format as outlined in Annex I.

REGULATION (EU) 520/2012 Regulation (EU) 520/2012 PERIODIC SAFETY UPDATE REPORTS Content All available data, focus on new information since the data lock point of the last PSUR Accurate estimate of the population exposed, volume of sales and prescriptions Qualitative and quantitative analysis of actual use v. approved indications Results of relevant assessments of the effectiveness of risk minimization activities MAHs shall not be required to include systematically detailed listings of ICSRs Case narratives shall be in the relevant risk evaluation section (signal or safety concern) Conclusions: need for changes and/or actions, implications for SmPC Unless otherwise specified single PSUR shall be prepared for all MPs with the same API Combinations: either separate or with the main API Format Annex II. The Agency may publish templates for the modules set out in Annex II

REGULATION (EU) 520/2012 Regulation (EU) 520/2012 POST-AUTHORIZATION SAFETY STUDIES (PASS) Scope PASS initiated/managed/financed by MAH imposed by NCAs, Agency or Commission MAH shall submit: study protocol, abstract of final study report, final study report English translation of title, abstract of protocol, abstract of the final study report Handling and storing of study information to ensure accurate reporting, interpretation and verification and confidentiality of the study subjects remains protected The Agency may publish templates for the protocol, abstract and final study report Definitions ‘Start of data collection’ – the date from which information on the first study subject is first recorded in the dataset or, the date from which data extraction starts ‘End of data collection’ – the date when the analytical dataset is completely available Format – Annex III.

ICH GUIDELINES PHARMACOVIGILANCE GUIDELINES: ICH A2A to E2F

GPvP GUIDELINES

MILESTONES 27/06/2013 Adoption of a proposal for fees for PV payable to the EMA Proposal for a Regulation of the European Parliament and of the Council on Fees payable to the European Medicines Agency for the Conduct of Pharmacovigilance Activities in Respect of Medicinal Products for Human use

BLACK SYMBOL 07-March-2013 COMMISSION IMPLEMENTING REGULATION (EU) No 198/2013 COMMISSION IMPLEMENTING REGULATION (EU) No 198/2013 Black Symbol to identify MPs that are subject to additional monitoring Patients and HCPs encouraged to report unexpected ADRs via national reporting systems.national reporting systems The black symbol shall be an inverted equilateral triangle Concept paperConcept paper for public consultation 11/2012 to 1/2013) Implementation: 31 December 2013 Stocks produced, packaged and labelled before Jan 2014 may continue to be placed on the market, distributed, dispensed, sold and used until stocks are exhausted.

FURTHER DEVELOPMENTS Transitional provisions: Commission Regulation (EEC) 540/95 on "suspected unexpected non-serious adverse reactions" ceases to apply to human MPs.Regulation (EEC) 540/95 One-year report on human medicines PV tasks of the European Medicines Agency Period covered: 2 July 2012 to 1 July 2013 Issue date: 02 May 2014 Author: European Medicines Agency Scope: Overview of PV-related activities such as assessment of new potential safety issues associated with medicines, regular PSURs and RMPs Further developments Some pharmacovigilance incidents triggered more changes: Directive 2012/26/EU (June 2013)2012/26/EU Regulation (EU) 2012/1027/EU (October 2013)2012/1027/EU Commission Delegated Regulation (EU) 357/2014 (April 2014)357/2014

MEDIATOR SCANDAL EMA permanently revokes marketing approval. Judiciary investigations and governmental accountability reviews are planned. Mediator first marketed in France, as add on therapy for hyperlipidaemia, diabetes with obesity. Benfluorex reassessed under a EU Directive (all per-1976 drugs), revised MA is not issued. Fenfluoramine is restricted because of CVS safety concerns. Benfluorex is unaffected. Fenfluoramine is withdrawn, benfluorex remains on the market. AFSSAPS revokes approval of benfluorex for diabetes in April, only to rescind the action 2 months later. Benfluorex placed under “official” PV investigation in France. Italian regulators also raise concern Two cases of CVS complications are reported in France. This is the year in which benfluorex should have been withdrawn, says the Inspection Générale des Affaires Sociales. Spanish regulators report a case of cardiac valvulopathy to EMA. Servier withdraws benfluorex in Spain and Italy, by not re-applying for MA. AFSSAPS begins another review. Approval for hyperlipidaemia, but not diabetes, is revoked. AFSSAPS suspends marketing of benfluorex in France, citing both efficacy and safety issues. Servier withdraws the drug worldwide. Estimated 3100 people were hospitalized and over 1300 died due to valvular insufficiency associated with benfluorex use in France from 1976 to 2009 1976 1987 1995 1997 1998 1999 2003 2007 2009 2010

GAP ANALYSIS & RESPONSE 2011 PV incidents: "Mediator case“ The Commission therefore promptly carried out a "stress-test" to check whether the pharmacovigilance rules adopted in 2010 would need to be further strengthened. This review identified the following gaps: GAP: Lack of automatic assessment of a PV issue at EU level in case of serious safety concerns. The procedure could only be initiated by Member States.  introduce an automatic urgent procedure for review at EU level, if there are serious safety concerns about MP authorized in more than one Member State. GAP: MAHs were not required to state the reasons for withdrawal of a MA or MP; therefore voluntary withdrawal led to unnoticed safety issues.  increase the transparency required by companies regarding the reasons for the withdrawal of a MP from the market, safety reasons can be easily identified GAP: MPs subject to post-authorization safety conditions were included in the public list of additional monitoring only if the Commission or a Member State's competent authority requested it. NCAs could decide on a case-by-case what to announce  MPs for which PASS are required as a condition of MA will be included on the list of medicines under increased monitoring.

Regulation (EU) No 357/2014 10/04/2014 - Delegated Regulation on PAES Specifies situations in which post-authorization efficacy studies (PAES) are required. Additional studies may be required to address certain well-reasoned scientific concerns, which could have a direct impact on the maintenance of the MA.

THANK YOU Contact: 1334 E Chandler Blvd No 5, Box A-19 Phoenix 85048, AZ, USA T: +1.480.409.0778 Email: veronikav@arete-zoe.comveronikav@arete-zoe.com Website: http://aretezoe.com/http://aretezoe.com/

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