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Pharmacovigilance during clinical developmentSAE reporting, ASUR and PSUR IFF Seminar, 21. February 2007

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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

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Agenda

1. Reporting of SAEs2. Annual Update Reports3. Periodic Safety Update Reports

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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.

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Adverse Events vs. Adverse Drug Reaction

AEs

ADRs

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Assessment

Sponsor has to perform evaluation of:

• Seriousness• Expectedness/listedness• Causality• Reportable

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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

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Expectedness/Listedness

Company Core Safety Information (CCSI) Listedness

Summary of Product Characteristics (SPC) Expectedness

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Causality

An assessment of the relationship between the drug and the ADR

Probably

Possibly

Not related

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Definition of SUSAR

• SuspectedEvaluated by sponsor and/or investigator as

possible/probable related to IMP

• UnexpectedEvaluated by sponsor as unexpected according to the

reference document

• Serious(death, life-threatening, hospitalisation, ect.)

• Adverse ReactionAny untoward and unintended response to an IMP

related too any dose administered

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Whom to report to?

MAH must report all relevant safety information to:– the concerned competent authorities– the Ethics Committees concerned– all investigators concerned

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Competent AuthoritiesWhat 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

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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

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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

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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

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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

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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

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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.

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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

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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

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Questions

Questions