Introduction to pharmacovigilance

MOHAMED ABOU-EL-ENEIN

MAY 2012

Introduction to pharmacovigilance
1) Definition: The science and activities relating to the detection, assessment, understanding and prevention of adverse drug reactions (ADRs) or any other medicine-related problem. 2) Regulations: The legal framework for pharmacovigilance of medicinal products for human use in the European Union (EU) is given in Regulation (EC) No 726/20041 and Directive 2001/83/EC2 on the Community code relating to medicinal products for human use, as last amended by Directive 2004/24/EC3 and by Directive 2004/27/EC4 (hereafter referred to simply as Directive 2001/83/EC). It should be noted that although Chapter 3 of Regulation (EC) No 726/2004 and Title IX of Directive 2001/83/EC contain the majority of pharmacovigilance provisions in the legislation, other measures directly relevant to the conduct of pharmacovigilance are found in other Chapters and Titles of those legislative texts. Adverse Drug Reaction: A response to a medicinal product that is noxious and unintended (Directive 2010/84/EU). ADR can lead to death, life-threatening, hospitalization or prolongation of existing hospitalization, persistent or significant disability and congenital anomaly/birth defect (Article 1(12) of Directive 2001/83/EC). In Europe, EMA estimates 197,000 deaths per year from ADRs (5th most common cause of death in hospital). Diagnosis of ADR: ADR can be Non-specific: clinical picture very similar with different drugs and non-pharmacologic causes (e.g. headache) Polymorphous: the same drug can cause different ADRs, on different organ classes (e.g. NSAIDs) Individual Susceptibility: gender, age, physiologic alterations, concomitant diseases and genetic causes Adverse drug reactions in Germany: The incidence of hospitalization due to at least 'possible' serious outpatient ADRs was estimated to be approximately 3.25%. Mean age of the 1834 patients was 71.0 years (SD 14.7). Most frequent ADRs were gastrointestinal hemorrhage (n=336) and druginduced hypoglycemia (n=270). Average inpatient length-of-stay was 9.3 days (SD 7.1). Average treatment costs of a single ADR were estimated to be approximately 2250. The total costs sum to 434 million per year for Germany. Major causes of ADRs: 4 groups of drugs cause more than 50% of ADRs: anti-platelets, diuretics, NSAIDs, anticoagulants 8 groups cause more than 30% of ADRs: opioid analgesics, beta-blockers, ACE-inhibitors, antidiabetics, positive inotropes, corticosteroids, antidepressants, CA antagonists.

3) Qualified Person Responsible for Pharmacovigilance: To ensure that the marketing authorization holder (MAH) has an appropriate system of pharmacovigilance in place in order to assume

responsibility and liability for his products on the market and to ensure that appropriate action may be taken when necessary, a QPPV should be appointed. The role of QPPV is Establishing and maintaining/managing the MAHs pharmacovigilance system; Having an overview of the safety profiles and any emerging safety concerns in relation to the medicinal products for which the MAH holds authorizations; Acting as a single contact point for the Competent Authorities on a 24-hour basis 4) Pharmacovigilance System: The Applicant for a marketing authorization is required to provide a detailed description of the system of pharmacovigilance and, where appropriate, of the risk management system which the Applicant will introduce (Article 8(3)(ia) of Directive 2001/83/EC). The system should be provided in Module 1/section 1.8.1 of the application dossier. The system is monitored by competent authorities. It should include QPPV: Name, contact details, CV and job description should be available Organization: Identification and location of the company units or other organizations where the principal global pharmacovigilance activities are undertaken also a High-level organization chart(s) and Flow diagrams indicating the flow of safety reports of different sources and types should be provided. Documented Procedures: The following list indicates topics that should usually be covered by written procedures. The activities of the QPPV The collection, processing and reporting of Individual Case Safety Reports (ICSRs) The collection, processing and reporting of Periodic Safety Update Reports (PSURs): The follow-up of report outcome of the case(s) Expedited reporting and electronic reporting Global pharmacovigilance activities applying to all products (safety profile of authorized medicines and pharmacovigilance planning) Responses to requests for information from regulatory authorities Internal audit of the Pharmacovigilance System Handling of urgent safety restrictions and safety variations Monitoring by competent authorities: Under EU legislation, to protect public health, Competent Authorities are obliged to implement pharmaceutical legislation and to ensure compliance with pharmacovigilance obligations. When non-compliance is detected, the necessary action will be judged on case-to-case basis. Action may be taken by the Agency, the Commission or the competent authority of Member States as appropriate. The action can be Education of the MAH on how to solve the non-compliance Inspection to detect the extend of the non-compliance Formal warning of the MAH Public naming of non-compliant MAH Variation, suspension or revocation of the marketing authorization

5) EU Risk Management Plan (EU-RMP): It is a risk management system designed is to ensure that the benefits of a particular medicine (or a series of medicines) exceed the risks by the greatest achievable margin for the individual patient and for the target population as a whole. This RMP contains two parts: A Safety Specification: The Safety Specification should be a summary of the important identified risks of a medicinal product, important potential risks, and important missing information. It should also address the populations potentially at risk. It includes a clinical section reporting the post-authorization (non-study) exposure. A non-clinical section should also discuss Toxicity (including repeat-dose toxicity, reproductive/developmental toxicity, nephrotoxicity, hepatotoxicity, genotoxicity, carcinogenicity) General pharmacology (cardiovascular, including QT interval prolongation, nervous system); Drug interactions Other toxicity-related information or data A Pharmacovigilance Plan: The plan is based on the safety specification and proposes actions to address the safety concerns identified. Within the Pharmacovigilance Plan the action plan for each safety concern should be presented and justified according to the following structure Safety concern Objective of proposed action(s) Action(s) proposed Monitoring by the Applicant/MAH for safety concern and proposed action(s) Milestones for evaluation and reporting

An evaluation for the need of risk minimization activities: Some safety concerns can be adequate addressed within the pharmacovigilance plan, but for others the risk may be of particular nature and seriousness that requires risk minimization plan. Example of a possible plan for a known teratogen could have the objective of avoiding any patient taking the drug becoming pregnant. A routine risk minimization activity might be to emphasize the need for effective contraception in the Summary of Product Characteristics and a recommendation that patients should have a negative pregnancy test before each prescription. One additional risk minimization activity might be to develop an educational pack to provide information to the patients on the risks of the medicine and the need for contraception Situations Requiring an EU-RMP: An EU-RMP may need to be submitted at any time of a products life-cycle i.e. during both the pre-authorization and post-authorization phases. In particular an EURMP should be submitted: With the application for a new marketing authorization for any product containing a new active substance; a similar biological medicinal product or a generic/hybrid medicinal product where a safety concern requiring additional risk minimization activities has been identified. With an application for a pediatric use marketing authorization (PUMA)

 With an application involving significant changes in a marketing authorization (unless the competent authority say it is not required) On request from a Competent Authority (both pre-and post-authorization); On the initiative of an Applicant/MAH when they identify a safety concern with a medicinal product at any stage of its life cycle. Product which is not in the above categories and seeking a new authorization via the centralized procedure may require a RMP: Known active substances Hybrid medicinal products where the changes compared with the reference medicinal product suggest different risks Bibliographical applications Fixed combination applications 6) Periodic Safety Update Report (PSUR): is intended to provide an update of the worldwide safety experience of a medicinal product to Competent Authorities at defined time points post authorization. Once a medicinal product is authorized in the EU, even if it is not marketed, the MAH is required to submit PSURs at 6-monthly intervals. Once marketed, 6-monthly PSUR submissions should be continued following initial placing on the market in the EU and until two full years of marketing experience in the EU has been gained. Then, PSURs should be submitted once a year for the following two years and thereafter at 3-yearly intervals. PSURs should also be submitted upon request of a Competent Authority or the Agency at any time after granting of the marketing authorization. The main focus of the PSUR should be the presentation, analysis and evaluation of new or changing safety data received during the period covered by the PSUR. For this purpose, analysis of adverse reaction reports, an overview of cumulative data, safety data from studies and other relevant safety information, as well as follow-up of any Risk Management Plan should be adequately addressed in the PSUR.

7) Individual Case Safety Reports (ICSRs): Medical and administrative data related to individual cases which qualify for expedited and periodic reporting should be provided electronically. According to the international regulations, a case narrative should be provided for all serious cases. This case narrative should be a medical report containing all known relevant clinical and related information, including patient characteristics, therapy details, medical history, clinical course of the event(s), diagnosis, adverse reactions including the outcome, relevant laboratory evidence (including normal ranges) and any other information that supports or refutes an adverse .

New pharmacovigilance legislation

Aims to promote and protect public health by strengthening the Europe-wide system for monitoring the safety and benefit-risk balance of medicines. Most of the legislation applies from July 2012

Activities of the new legislation: 1) Collection of key information on medicines Risk management plans: In the European Union, companies submit a risk management plan at the time of application for a marketing authorization. The plan includes information on how the medicine will be monitored for safety during its lifetime and describes risk minimization activities. In February 2012, the Agency will publish a draft good pharmacovigilance practice (GVP) module on risk management plans for consultation. Periodic safety update reports (PSURs): PSURs are documents that provide an evaluation of the benefit-risk balance of a medicine. They are submitted by marketing authorization holders at defined periods during the post-authorization phase. In February 2012, the Agency will publish a draft GVP module on PSURs for consultation. During 2012, the agency will implement new procedures related to PSURs for centrally authorized medicines. Beyond 2012, work will focus on PSURs for nationally authorized medicines. Post-authorisation safety and efficacy studies (PASS/PAES): A PASS is a study of an authorized medicine which identifies, characterizes or quantifies a safety hazard, confirms the safety profile of the medicine, or gauges the effectiveness of risk management measures during its lifetime. A PAES aims to clarify the efficacy for a medicine on the market including efficacy in everyday medical practice. The purpose of the information in a PASS/PAES is to support regulators in decision-making on the safety and benefit-risk profile of a medicine. In February 2012, the Agency will publish a draft GVP module on PASS and guidelines on PAES for consultation. From July 2012 Pharmacovigilance Risk Assessment Committee (PRAC) will be responsible for approving new PASS protocols. During 2012, protocol approval and results management for centrally authorized medicines will take place. Beyond 2012, the agency will focus on nationally authorized medicines. Electronic submission of core medicine information by pharmaceutical industry: The pharmaceutical industry is required to provide the Agency with key information on all authorized and registered medicines in line with Article 57 of the new regulation. The deadline for submission of information by industry is July 2012. Reporting by patients: The legislation introduces the right of individual European citizens to report suspected side effects from medicines directly to national medicine regulatory authorities.

2) Better analysis and understanding of data and information EudraVigilance and signal detection: EudraVigilance, a system designed for collecting reports of suspected side effects. These reports are used for evaluating medicines during their development and monitoring their safety following their authorization in the European Economic Area (EEA). As of July 2012, the Agency will begin to operate a revised signal detection process for centrally authorized medicines. For nationally-authorized medicines the Agency will further improve access to EudraVigilance data for national medicine regulatory. Additional monitoring: During 2012, the Agency will work with the European Member States to establish the first list of medicines subject to additional monitoring. This list, and the subsequent changes to package leaflets for medicines on the list, will encourage reporting of suspected side effects and increase transparency for patients on medicines that are being closely monitored. IT systems to support processing and analysis of data: The development of IT systems requirements will be done in coordination with key stakeholders such as national medicines regulatory agencies and pharmaceutical industry.

3) Regulatory action to safeguard public health: The legislation increases the opportunities for quick regulatory action when public health is at risk. Scientific committees and decision-making: A new Pharmacovigilance Risk Assessment Committee (PRAC) will begin meeting from July 2012 with monthly meetings from September 2012. The PRAC will focus on the planning, assessment and monitoring of safety issues with human medicines. The Committee for Medicinal Products for Human Use (CHMP) will start to adopt opinions based on recommendations from the PRAC. Also, the existing Co-ordination Group for Mutual Recognition and Decentralized Procedures Human (CMDh) will lead on decision-making based on recommendations from the PRAC for nationally-authorized medicines. Strengthening referral procedures: A referral is a procedure used to resolve disagreements and address concerns. In a referral, the European Medicines Agency is requested to conduct a scientific assessment of a particular medicine or class of medicines on behalf of the EU. This assessment procedure is conducted through the PRAC and/or CHMP in conjunction with the CMDh in the case of nationally authorized products. Final decisions can result in changing the product information (summary of product characteristics/patient information leaflet), restricting the use of the medicine or withdrawing the medicine from the market. During 2012, the Agency will implement a major new referral procedure (known as the urgent Union procedure) specifically designed to rapidly assess significant emerging safety issues linked with a medicine available in the EU regardless of its initial authorization route (being centralized or national authorization).

4) Communication with stakeholders: the legislation aims to increase public confidence in the safety monitoring system by allowing the public access to agendas and minutes of regulatory meetings on safety issues. Online publishing of information: During 2012, the Agency will begin publishing the agendas and minutes of the PRAC, CMDh and CHMP and the assessments, approvals, recommendations, opinions and decisions from the PRAC, CMDh and CHMP through its corporate website at www.ema.europa.eu. Coordination of safety messages: The Agency will support the coordination of safety announcements for nationally authorized products with European Member States. This is to ensure the delivery of consistent safety advices on medicines that are authorized through national procedures but available in more than one Member State. Public hearings: 2012 will see the introduction of public hearings for referrals which fall within the urgent Union procedure when this is considered necessary by the PRAC.