H. Lundbeck A/S21-Sep-151 Pharmacovigilance during clinical development SAE reporting, ASUR and PSUR IFF Seminar, 21. February 2007

H. Lundbeck A/S21-Sep-152 Recording of ADRs EU Directive 2001/83/EC: The Marketing Autorisation Holder (MAH) shall be required to maintain detailed records of all suspected adverse reactions occuring either in the Community or in a third country. MAH shall have a global ADR system

H. Lundbeck A/S21-Sep-153 Agenda 1.Reporting of SAEs 2.Annual Update Reports 3.Periodic Safety Update Reports

H. Lundbeck A/S21-Sep-154 Directive 2001/20/EC and Guidance EU Clinical Trial Directive 2001/20/EC (4 April 2001): This Directive came into force 1 May 2004 Safety articles: –Article 2: Definitions –Article 16: Notification of Adverse Events –Article 17: Notification of Serious Adverse Reactions –Article 18: Guidance concerning reports Detailed guidance on: –The European clinical trials database (EUDRACT database) –The European database of SUSARs –Collection, verification and presentation of adverse reactions reports arising from clinical trials.

H. Lundbeck A/S21-Sep-155 Adverse Events vs. Adverse Drug Reaction AEs ADRs

H. Lundbeck A/S21-Sep-156 Assessment Sponsor has to perform evaluation of: Seriousness Expectedness/listedness Causality Reportable

H. Lundbeck A/S21-Sep-157 Serious Adverse Reaction Definition A serious adverse reaction is any untoward medical occurrence or effect that at any dose: –results in death, –is life-threatening, –requires hospitalisation or prolongation of existing hospitalisation, –is a congenital anomaly or birth defect, –is medial important

H. Lundbeck A/S21-Sep-158 Expectedness/Listedness Company Core Safety Information (CCSI) Listedness Summary of Product Characteristics (SPC) Expectedness

H. Lundbeck A/S21-Sep-159 Causality An assessment of the relationship between the drug and the ADR Probably Possibly Not related

H. Lundbeck A/S21-Sep-1510 Definition of SUSAR Suspected Evaluated by sponsor and/or investigator as possible/probable related to IMP Unexpected Evaluated by sponsor as unexpected according to the reference document Serious (death, life-threatening, hospitalisation, ect.) Adverse Reaction Any untoward and unintended response to an IMP related too any dose administered

H. Lundbeck A/S21-Sep-1511 Whom to report to? MAH must report all relevant safety information to: –the concerned competent authorities –the Ethics Committees concerned –all investigators concerned

H. Lundbeck A/S21-Sep-1512 Competent Authorities What and when to report? Clinical trials: –Fatal and life-threatening SUSARs: no later than 7 calendar days –Other SUSARs no later than 15 calendar days Post-marketing: no later than 15 calendar days The clock starts (day 0) on the date when any personnel of the MAH first receive a case report that fulfill the minimum criteria

H. Lundbeck A/S21-Sep-1513 Ethics Committees (ECs) Only receive individual reports of SUSARs that occurred in that Member State, provided that: –All SUSARs from Member States and third countries are reported at least quarterly as a line listing and a brief report. –Other changes increasing the risk to subjects should be provided as soon as possible within 15 days

H. Lundbeck A/S21-Sep-1514 Investigators Line listings of SUSARs in periods as warranted by the nature of the clinical development project and the volume of SUSARs generated. Accompanied by a concise summary of the evolving safety profile of the IMP The blind should be maintained when possible and appropriate

H. Lundbeck A/S21-Sep-1515 Annual Safety Report - content ADRs from clinical trials produced on one drug substance. –Report on subjects’ safety –Line listing of all SARs (unblinded) –Aggregated summary tabulation of SARs (unblinded) May trigger amendments to study protocol, changes and updates to the IB

H. Lundbeck A/S21-Sep-1516 Annual Safety Report - reporting To concerned competent authorities and Ethics Committees Reporting responsibility starts with the first authorisation in any Member State – the date is used for cut-off date for data to be included MAH should submit the report within 60 days of data lock point

H. Lundbeck A/S21-Sep-1517 Directive 2004/27/EC and Guidance Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use Article 101 to 108 Into force 20 November 2005 Guidance documents: Volume 9A of The Rules Govering Medicinal Products in the European Union of January 2007 –Pharmacovigilance for Medicinal Products for Human Use ICH E2C incl. Addendum, latest of Febuary 2003

H. Lundbeck A/S21-Sep-1518 Periodic Safety Update Report (PSUR) Definition –An update of the world-wide safety experience with a medicinal product –A condition for marketing authorisation –Prepared for Regulatory Authorities Objective –Safety of the product is in accordance with previous knowledge. –To indicate whether changes should be made to the product information.

H. Lundbeck A/S21-Sep-1519 PSUR - Source of information Adverse drug reactions (ADRs) from: spontaneous notifications marketing authorisation holder sponsored clinical studies or named patient (compassionate) use literature reports on ADRs exchanged between contractual partners (e.g. licensors-licensees) data in special registries epidemiological databases

H. Lundbeck A/S21-Sep-1520 PSUR - Reporting PSURs should be submitted at the following times from the International Birth Date: –immediately upon request –6-monthly for the first 2 years after authorisation –annually for the subsequent 2 years –at the first renewal –thereafter 5-yearly at renewal. MAH should submit the report within 60 days of data lock point

H. Lundbeck A/S21-Sep-1521 Questions