European Clinical Trial

Safety Focus (2013)

Presented by:

Vaska Tone

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Legislation and Definitions Investigator Responsibilities Sponsor Responsibilities Periodic Reporting Ethics Committee Responsibilities Competent Authority Responsibilities

Clinical Trial Safety

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European Legislation and Guidelines

Directive 2001/20/EC Article 16(4) Detailed Guidance on the collection, verification and presentation of

adverse reaction reports arising from clinical trials on medicinal products for human use (Apr 06)

Detailed guidance on the European database of Suspected Unexpected Serious Adverse Reactions (SUSARs)

(Eudravigilance - Clinical Trial Module Apr 04)Directive 2001/83/EC Articles 17(1) and (2) ICH E2A, E2B(R3), E6

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ICH E2A Definitions

Adverse Event (AE) Any untoward medical occurrence in a patient or clinical investigation

subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment

Adverse Drug Reaction (ADR) Pre-approval: All noxious and unintended responses to a medicinal

product related to any dose should be considered adverse drug reactions

Marketed: A response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function

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ICH E2A Definitions

Serious AE or ADR A serious adverse event or drug reaction is any untoward medical

occurrence that at any dose:o Results in deatho Is life-threateningo Requires inpatient hospitalisation or prolongation of existing

hospitalisationo Results in persistent or significant disability/incapacity, oro Is a congenital anomaly/birth defect

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‘Important medical events’ or ‘events of interest’ or medical significance’ may be treated as serious

ICH E2A Definitions

SevereSevere is used to describe the ‘intensity’ of a specific event, the event itself may be relatively minor e.g. severe headache

SeriousSerious is based on patient/event outcome or action criteria associated with an event that poses a threat to life or functioning

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‘Seriousness’, not severity serves as a guide for defining regulatory reporting obligations

ICH E2A Definitions

Expectedness An unexpected ADR is one, the nature or severity of which, is not

consistent with information in the relevant source documents

i.e. Investigator’s Brochure (IB) or Summary of Product Characteristics (SmPC; if marketed)

Reports, which add significant information on specificity or severity of a known, already documented serious ADR constitute unexpected events

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Reporting of Serious ADRs

Identification of SUSARs Suspected, Unexpected, and Serious

What not to report Serious, expected reactions Non-serious adverse drug reactions (expected or not)

Active comparators or placebo SUSARs to be reported to Competent Authority (CA) and Ethics

Committee (EC) of concerned Member State (i.e. EU Country). Recommended to inform Marketing Application Holder (MAH)

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Investigator Responsibilities

Timelines for notification Immediately (within 24hrs of PI awareness) to sponsor, followed by

detailed written report

Information Suspected IMP Identifiable subject (study subject code no.) Serious and unexpected event with reasonable suspected causal

relationship Identifiable reporting source (Healthcare Professional (HCP)) Study protocol number/EudraCT no.

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Sponsor Responsibilities

Fatal or Life-threatening SUSARs must be reported to the CA and EC within 7 calendar days in the concerned EU country

Follow-up must be reported within a further 8 calendar days

Other SUSARs & SAEs must be reported to CA and EC as soon as possible, but no later than within 15 calendar days

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Sponsor Responsibilities

Assessment of Seriousness Refer to definition and any other requirements for product i.e. events

of significant interest

Assessment of Expectedness Refer to current IB and protocol, review for listed events. If marketed

product refer to SmPC in country of event

Assessment of Causality Investigator’s assessment takes priority and cannot be changed by

sponsor. If Sponsor’s opinion differs, both opinions must be documented

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Processing of SUSARs

‘Valid’ cases are entered into the safety database Narratives must be written for reporting based on

investigator’s information CIOMS I forms (or equivalent – MedWatch in the USA) must

be completed and reviewed by a physician or qualified person before submission

Safety database must be reconciled with clinical database for all serious events

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Electronic Reporting

SUSARs must be reported via EudraVigilance – the EMA electronic safety (PV) database

Data elements given in ICH E2B(R3) Current version of the Medical Dictionary for Regulatory

Activities (MedDRA) to be used for coding adverse reaction terms

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Blinded Studies

Assess seriousness, expectedness and causality assuming the event is related to the IMP

If considered a SUSAR, blind must be broken for reporting Maintain blind for biometrics, data-analysis and reporting of

results Investigators to be unblinded only if relevant for the safety of

the subject

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High Morbidity/Mortality Studies

Efficacy end-points may be SUSARs Study blind may be compromised Agree with CAs reporting procedure for disease-related events Appoint independent Data Safety Monitoring Board (DSMB) Reporting procedure and role of DSMB to be described in the

protocol

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Informing Investigators

Distribute aggregate line-listing of SUSARs at intervals

Provide summary of evolving safety profile

Significant safety issues should be communicated as soon as possible

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Periodic Reporting

Sponsors must submit annually, or on request, a safety report to CA and EC in concerned MS

Purpose is to assess and monitor the safety conditions of subjects in a clinical trial

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Reporting Timeframes

Annually from date of first Clinical Trial Authorisation in a MS

Anniversary is ‘data lock point’ for all new data

Report to be submitted within 60 days of data lock point

If multiple trials with same IMP, only one report required

For First in Man (FIM) or short-term trials, safety report to be submitted within 90 calendar days of end of trial

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Annual Safety Report

Part 1: Analysis of the subjects’ safety in the trial Part 2: Line listing of all suspected serious ADRs (including

SUSARs) Part 3: Aggregate summary table of SSARs

Tabled by System, Organ, Class (SOC) System: Anatomical or physiological e.g. cardiac disorder Body Organ: Part of the body affected : e.g. heart Class: Specific aspect of effect: e.g. cardiac arrest or

myocardial infarction or palpitations

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Ethics Committee Responsibilities

Review of Serious and Unexpected ADRs to continuously assess the risk/benefit to subjects

Receipt of Individual Case Safety Reports and 6-monthly line listings for review

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Competent Authorities Responsibilities

Continuous monitoring of risk to subjects

Ensuring other CAs are informed of safety issues

Post-marketing pharmacovigilance

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Post-marketing Good Vigilance Practices

The European Union member states are supposed to adhere to the GVPs noted in what is known as Volume 9A of the European Directives and as of July 2012 the EU GVP Modules (total of 16, but not are all final)

Post-marketing GVPs come into effect once the products are approved for marketing either by the:

Centralized procedure Decentralized procedure National procedures.

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Marketing Approvals - Centralized

Centralized Procedure:o Allows applicants to obtain a marketing authorization that is valid

throughout the EU

o Application is sent directly to the European Medicines Agency, to be assessed by the Committee for Medicinal Products for Human Use (CHMP)

o Is the basis for what is known as the “International Birthdate” of the product

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Marketing Approvals - Decentralized

Decentralized Procedure:o Market a product in various EU countries and for which the

product has not yet received an approval in any EU country.

o An identical application for marketing authorization is submitted simultaneously to the Competent Authorities (CAs) of the Reference Member State (the country making the scientific evaluation of the application) and of the Concerned Member States (where the product will be marketed).

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Marketing Approvals – National

National Procedure:o Is only to be registered in one country and not intended to be

registered elsewhere

o The country may not have been part of the decentralized procedure and would need to have country specific authorization

o The country might not be an EU member at the moment, but may be part of it at some later time, but wish to market

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GVP - reporting

Serious Adverse Events – ALL including death: 15 DAYS (different than SUSARs which require 7 day report)

Non-Serious Adverse Events – unexpected (unlabeled) 90 Days

Non-Serious Adverse Events – expected In the Periodic Safety Update Report (PSUR)

Person held accountable for the adherence of reporting is the EU Qualified Person for Pharmacovigilance (QPPV)

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PSURs

PSURs are very lengthy and require input from many departments including safety, marketing, GMP quality etc.

After initial registration and upon placement of the product on the market: Every 6 months for the first 2 years Annually for the next 3 years Then every 5 years

However, many EU member countries have a local regulation mandating renewal of registration every 3 years, therefore it is typical to have an updated PSUR submitted with the renewal documentation (requires what is known as an addendum to the PSUR)

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Questions?

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