Pharmacovigilance

in Clinical Trials

Version 04 Feb 2021

In this training course you will learn

• What is pharmacovigilance?

• What is the pharmacovigilance responsibility of the investigator in a clinical

trial?

• What is the pharmacovigilance responsibility of the sponsor in a clinical

trial?
Introduction
Pharmacovigilance - Introduction

• Pharmacovigilance – also called Drug safety

• Pharmakon (Greek for drug)

• Vigilare (Latin for to keep watch)

• Process and science of monitoring the safety of medicines and taking

action to reduce the risks and increase the benefits of medicines

EMA Guideline on good pharmacovigilance practices (GVP)

Pharmacovigilance – WHY?

All things are poison, and nothing is without poison; only the dose permits
something not to be poisonous.

Paracelsus (1493-1541)
Thalidomide case

• In the late 50’s thalidomide was sold as OTC medication to treat several
conditions, including morning sickness in pregnant women

• In 1961 Dr. McBride, Australian obstetrician and Dr. Lenz, German

paediatrician, reported about birth defects/malformations

McBride W. 1961. Thalidomide and congenital malformations. Lancet 1:358

Lenz W. 1962. Thalidomide and congenital abnormalities. Lancet 1:271–272
The birth of modern Pharmacovigilance

• Thalidomide-caused birth defects revealed the gaps in the drug approval

systems in place.
• The tragedy caused the approval of new regulations to ensure that
• medicinal products were tested in animals before their use in humans
• companies had systems in place to detect toxicities and act promptly
• Thalidomide is still marketed, but with a strict Risk Management Plan.
Positive balance

• No medication is free of toxicities

• Benefit of use must be greater than risks

• Better knowledge = better decisions

What is Pharmacovigilance*?

• Science and activities relating to the detection, assessment, understanding and prevention of
adverse effects or any other medicine-related problem.

• In line with this general definition, underlying objectives of pharmacovigilance in accordance with the
applicable EU legislation are:
• preventing harm from adverse reactions in humans arising from the use of authorised medicinal products within or outside
the terms of marketing authorisation or from occupational exposure; and
• promoting the safe and effective use of medicinal products, in particular through providing timely information about the
safety of medicinal products to patients, healthcare professionals and the public.
• Pharmacovigilance is therefore an activity contributing to the protection of patients’ and public
health.

* As per Guideline on good pharmacovigilance practices (GVP) – Annex I EMA/876333/2011 Rev. 1

Pharmacovigilance includes:

• Adverse drug reactions

• Interactions with other medicinal products
• New effects of a medicinal product
• Lack of efficacy of medicinal product
• Misuse
• Dependence, abuse
Steps of Pharmacovigilance

• Detection
• Assessment
• Understanding
• Prevention
Definitions

• Adverse Event (AE)

• Adverse Drug Reaction (ADR)
• Serious Adverse Event (SAE)
• Serious Adverse Drug Reaction (SADR)
• Reference Safety Information (RSI)
• Suspected Unexpected Serious Adverse Reaction (SUSAR)
Adverse Event (AE)

• Any untoward medical occurrence in a patient or clinical trial subject

administered a medicinal product and which does not necessarily have a
causal relationship with this treatment [Dir 2001/20/EC Art 2(m)].
• An adverse event can therefore be any unfavourable and unintended sign
(e.g. an abnormal laboratory finding), symptom, or disease temporally
associated with the use of a medicinal product, whether or not considered
related to the medicinal product.
Adverse Drug Reaction*?

• A response to a medicinal product which is noxious and unintended

• Response in this context means that a causal relationship between a
medicinal product and an adverse event is at least a reasonable possibility

* A.k.a. Adverse reaction, Adverse effect, Suspected adverse (drug) reaction, Undesirable
effect
AE vs ADR

If the AE is considered related to the medicinal product, it is

Reaction called an adverse reaction
Relatedness

Adverse
Event
“Temporal correlation does not imply causation”

• Adverse event: Temporal correlation

• Adverse reaction/effect: Causality

Are the rabbit and the dog out running at the same time? (Temporal correlation)
Or is the rabbit running because the dog is chasing it? (Causality)
 SERIOUS Adverse Event

• A serious adverse event (experience) or reaction is any untoward medical occurrence

that at any dose:
• results in death,
• is life-threatening,
The term "life-threatening" in the definition of "serious" refers to an event in which the patient was at risk of death at the time of the event; it
does not refer to an event which hypothetically might have caused death if it was more severe.
• requires inpatient hospitalisation or prolongation of existing hospitalisation,
• results in persistent or significant disability/incapacity
• is a congenital anomaly/birth defect
• Medically significant event
• Any suspected transmission via a medicinal product of an infectious agent is also
considered a serious adverse reaction

NOTE FOR GUIDANCE ON CLINICAL SAFETY DATA MANAGEMENT: DEFINITIONS AND STANDARDS
FOR EXPEDITED REPORTING (CPMP/ICH/377/95)
AE vs SAE

If the AE is considered serious according to the defined criteria

SAE (death, hospitalisation, etc.), it is an SAE
Seriousness

Adverse
Event
Serious Adverse Drug Reaction (SADR)

• An AE that is considered
• serious (as per defined criteria)
AND
• possibly related to the medicinal product
Reference Safety Information (RSI)

• Reference safety information, i.e. the known safety information / adverse

reactions for a product

• The Investigator’s Brochure (IB) or Summary of Product Characteristics

(SmPC) outline which adverse reactions are to be considered as expected
adverse reactions, and the frequency and nature of those adverse reactions
Reg (EU) No 536/2014 Annex 1.E.30

• Summary of Product Characteristics (SmPC) is most commonly used as RSI in investigator initiated
trials testing authorised medicinal products in accordance with the marketing authorisation
SUSAR: Suspected Unexpected Serious Adverse Reaction

• Is the reaction known (included in the RSI)?

• If no, the event is considered “Unexpected”

Understanding the SUSAR concept – start from the last word and move
backwards
• The event is suspected to be related  Suspected Adverse Reaction
• And the event is serious  Serious Adverse Reaction
• And the event is unexpected 
Suspected Unexpected Serious Adverse Reaction (SUSAR)
Assessments

SUSAR

Expectedness
Expectedness
SAE Serious
ADR

Seriousness
Reaction
Relatedness

Adverse
Event
Adverse
Event
Legal framework in the EU/Norway

• Good Pharmacovigilance Practices (GVP)

• Regulations and guidelines are collected at the EMA web site

• Clinical trials:
• Directive 2001/20/EC (valid until 536/2014 is implemented)
• Regulation 536/2014 (to be implemented in Dec 2021?)
• FOR-2009-10-30-1321: Forskrift om klinisk utprøving av legemidler til mennesker (to
be updated when 536/2014 is implemented)
Investigator’s Responsibilities
Responsibilities

• Competent Authority
• Detection
• Assessment
• Sponsor
• Understanding
• Investigator • Prevention
• Patient
Responsibilities

• Detection

• Sponsor • Assessment
• Understanding
• Investigator
• Prevention
Investigator

• Detection
• SAE reporting, AE collection
• Assessment
• Relatedness
• Expectedness
• Understanding
• Investigator’s brochure
• Prevention
• Information to patients and clinical trial subjects
• Compliance with protocol
What must be reported?

• Minimum elements to make a case valid (from investigator):

• An identifiable patient (patient number…)
• A product (or a study number and randomization code, for blinded studies)
• An event
• A reporter (to be able to ask for more information)
What must be reported?

• Causality assessment:
• Is the event considered to be caused by the investigational medicinal product?
• This assessment is made by both investigator and sponsor

• Further desired elements:

• Severity
• Seriousness criteria
• Date of onset
• Date of last dosing of investigational medicinal product
Severity assessment

• Grading of event
• e.g. mild – moderate – severe – life threatening

• Several AE grading scales

Examples:
• National Cancer Institute’s
Common Terminology Criteria for Adverse Events (NCI’s CTCAE; for oncology
studies, see next slide)
• FDA/CEBR (for vaccine trials)
• WHO
NCI’s CTCAE

• Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic

observations only; no intervention indicated
• Grade 2 Moderate; minimal, local or noninvasive intervention indicated;
limiting age-appropriate instrumental activities of daily living (ADL)
• Grade 3 Severe or medically significant but not immediately life
threatening; hospitalization or prolongation of hospitalization indicated;
disabling; limiting self care ADL
• Grade 4 Life-threatening consequences; urgent intervention indicated.
• Grade 5 Death related to AE
NCI’s CTCAE
Note difference between severe and serious

• Serious – as per defined criteria (e.g. hospitalisation, death, etc.)

• Severity – grading of event (e.g. mild – moderate – severe)
Reporting Time Frames

• Investigator  Sponsor

• AEs
• Report as soon as possible (to allow for continuous safety assessment)
• Recorded in the CRF

• SAEs
• Report within 24 hours of becoming aware of the event
• Often separate report SAE report form to collect required information
Documentation

• All AE/SAE information must be verifiable in source documents!

• If lab reports or other documentation is sent to sponsor as supporting
documents to the SAE report, remember to remove all personal identifiers.
Assessments

Reaction
Relatedness

Recording in CRF
Adverse
Event
Assessments – reporting

SAE

Seriousness
Reaction
Relatedness

Adverse
Event
Recording in CRF
Adverse
24h notification required
Event
Further AE reporting details

• Follow AE reporting requirements as described in the protocol

• Events already described in medical history are not AEs

• Changed severity or frequency of events in medical history need to be
reported as AEs

• If an AE changes severity during the course (e.g. going from moderate to

severe), only one AE should be reported with the maximum severity (and
not one moderate AE and another severe AE) (unless protocol defines it
differently)
Sponsor’s Responsibilities
Sponsor

• Detection
• Clinical trial notifications (AE/SAE reports)
• Assessment
• SAE assessment (SUSAR), AE assessment/signal detection, DSUR, Investigator’s
Brochure, Data Monitoring Committee
• Understanding
• Ongoing risk assessment, Data Monitoring Committee, (DSUR)
• Prevention
• Information to patients and clinical trial subjects
• Detailed information in protocol
Planning phase

• Clinical Trial Protocol

• Need for a Data Monitoring Committee?
• Who will act as Medical Monitor
• Who will take care of SUSAR reporting?
• What is the Reference Safety Information?
Clinical Trial Protocol

• Must describe in detail all research procedures, summarize the scientific

rationale, and the product characteristics

• Summary of the known and potential risks and benefits, if any, to human
subjects.
Clinical Trial Protocol – GCP requirements

GCP section 6.8 Assessment of safety

• Specification of safety parameters.

• The methods and timing for assessing, recording, and analysing safety
parameters.
• Procedures for eliciting reports of and for recording and reporting adverse
event and intercurrent illnesses.
• The type and duration of the follow-up of subjects after adverse events.
Clinical Trial Protocol

• Emergency contacts should be included, or a clear guidance given

(supporting documentation, web page…)

• Define expedited reporting requirements

• Must all SAEs be reported to sponsor within 24 hours?

• Define other reporting requirements

• From when should AEs be reported?
• How should changes in severity be reported?
• How is hospitalisation defined? (Often: >24 hours)
Risk Assessment

• According to ICH-GCP-R2 risk assessment for a clinical trial should be

done as early as possible and mitigations included in the clinical trial
protocol and/or other study actions

• Risks to be assessed:
• Risks to participant safety associated with the intervention(s) being tested
• Risks associated with design and methods

• Ongoing evaluation (review and update of risk assessment at regular

intervals or in case of e.g. a substantial amendment)
Risks related to safety reporting

• Possible risk adaptations to safety reporting:

• selective recording and reporting of adverse events

• adaptations to expedited reporting from the investigator to the sponsor, for certain
serious adverse events.

• Requirements:
• Justification in protocol
• Supported by risk assessment
Examples (study specific risk assessments required)

• Neutropenia is an expected event that requires hospitalisation in oncology

trials. Protocol can define that these events are not to be reported
expeditely as SAEs, but rather as regular AEs in the CRF.

• Risk assessment justifies that AEs should be collected only after the
investigational medicinal product has been administered and not from the
time of informed consent for study participation.
Data Monitoring Committee (DMC)

• Groups of independent experts that review study data in an unblinded way

• Issues recommendations to the study sponsor
• Procedures must be documented in a charter
DMC Charter

• The charter will be signed by all members BEFORE starting the reviews
• The charter contains:
• Stopping rules
• Safety issues
• Lack of efficacy (futility)
• Overwhelming evidence of efficacy
• Voting procedures: Open & closed sessions
• Meeting frequency
• Data provided and format
DMC

• Recommendations are documented, and part of the Trial Master File

• DMC will review safety data

• DMC may review efficacy data at pre-determined points
Need a DMC?

• Consider indication, study endpoint(s), study duration as well as study

population and available knowledge about the investigational medicinal
product.

• A DMC is usually not needed in low risk clinical trials.

Need a Medical Monitor?

• YES
Responsibilities of a Medical Monitor

• Provide input to clinical trial protocol design and risk assessments

• Review and analyze safety (and efficacy) data, incl. SAE assessments

• Project leader/national co-ordinating investigator can act as Medical

Monitor
Safety reports during the study

• SAE processing – SUSAR reporting

• Line listings to investigators
• Urgent safety measures
• Annual safety report (DSUR)
• IB updates (if IB is in use for the clinical trial)
SAE processing

• SAEs received from investigator within 24 hours of investigator becoming

aware

Sponsor (Medical Monitor) must do:

• Causality assessment
• Can rely on investigator’s assessment
• Or do separate assessment in addition

• Expectedness assessment
• Is the event included in the Reference Safety Information (IB or SmPC)?
Causality Assessment

• Is there a causal relationship between medication and event?

YES/NO

• Several methods to assess relatedness

• Medical experience
• Structured scoring systems taking into consideration, i.a.
• Temporal association
• De-challenge/Re-challenge
• Mechanism of action
• Other explanation
Reasonable possibility

Definitely not related

Unlikely related
• Not related

Likely related
Definitely related • Related

If the investigator can choose between several options when assessing causality,
sponsor should up-front define which assessments are to be considered as “not
related” and “related”  important from a regulatory reporting perspective
Causality assessment

• Sponsor can never downgrade a causality assessment

Assessments

SUSAR

Expectedness
Expectedness
SAE Serious
ADR

Seriousness
Reaction
Relatedness

Adverse
Event
Adverse
Event
SUSAR: Suspected Unexpected Serious Adverse Reaction

• If the SAE is unexpected and related, it is a SUSAR

• If the investigator or the sponsor considers the SAE as “Related”, the

event is considered related (i.e. the sponsor can not downgrade an event).
SUSAR Reporting

• In case of SUSAR, expedited, unblinded reporting to:

• Competent Authorities* via Eudravigilance

• Additional requirement to inform:

• Ethics Committees (unless local regulations differ)
• Investigators

* Competent authorities (CA) = Statens Legemiddelverk or similar for other countries

Reporting Time Frames

• Sponsor  Competent Authorities (Eudravigilance database)

• Fatal or life threatening SUSARs

• Within 7 days of becoming aware
• Follow-up information within 8 days thereafter
• Other SUSARs
• Within 15 days

• But always as soon as possible

Reporting Time Frames*

• Sponsor  Ethics Committees, if applicable

• Each Ethics Committee will have different requirements

• E.g. all SUSARs in study, or in country, or just site or none
• Norway: None

*Slide not applicable after implementation of 536/2014. With 536/2014 the

competent authorities will obtain EC comments to SUSARs
Reporting Time Frames

• Sponsor  Investigators
• Line listings of blinded SUSARs
• In periods as warranted by the nature of the clinical development project and the volume of
SUSARs generated.
• Should be accompanied by comments on how/if the SUSARs changes the safety profile of
the test product

• IB update
• Annual review
Blinded Data - Investigators

• Unblinding the treatment of a patient has a high impact on the validity of

the data.
• Should only be done if knowing the treatment is essential in managing the
event (e.g. antidots, interactions)
• Even in those cases, the investigator is encouraged to contact the sponsor
before making a final decision
• Any unblinding must be properly documented (incl. rationale, date, name
and signature of person unblinding) and sponsor must be informed
Need to unblind?

• Competent authorities require (with some exceptions) unblinded SUSAR

reports

• Safety team at sponsor should unblind treatment to decide reporting “path”

even if investigator did NOT unblind the treatment
• NB! If the sponsor representative is actively involved in the clinical trial, someone else
should unblind for reporting.

• Study team should remain blinded to treatment allocation

Which SUSARs should be reported?

• If unblinding reveals that the SUSAR occurred in a patient receiving

placebo, expedited reporting to the competent authorities is rarely required
(exception: e.g. excipient reactions)

• Remember that reporting of SUSARs for active comparators is required

Blinded studies: Reporting to CA, ethics committees (ECs) and investigators

Report unblinded to
Test product
CA + EC
SUSAR
Break blind Report unblinded to
CA+ EC
Control or Re-assess
Placebo criteria
Report
blinded to Treat as SAE
investigators

• Reporting all cases to investigators maintains the blind

• But reporting placebo cases to CAs and ECs is misleading and inappropriate
Eudravigilance (EV)

• Sponsors must submit SUSAR reports to competent authorities via

Eudravigilance
Eudravigilance

• European Union Drug Regulating Authorities Pharmacovigilance

• Safety database of the European Medicines Agency (EMA)

• Two modules
• EVPM: Post Authorisation
• EVCTM: Clinical Trials
• The cases are entered
• Automatically, through a EV Gateway (safety database “communicates” directly with
Eudravigilance)
• Manually, through EVWeb (web based solution – preferred option if you have a low
number of anticipated SUSARs)
Eudravigilance

• Different types of organisations in Eudravigilance

• Category III: Non commercial sponsors

• All sponsors (institutions) have to

• Be registered in the EMA organisation database, SPOR
• Have a Responsible Person (RP) for Eudravigilance reporting
• The RP can delegate actual reporting of SUSARs

SPOR = Substances, products, organisations and referentials

Eudravigilance

• To use Eudravigilance, the sponsor must

• Have at least one trained user (unless using a 3rd party, e.g. Clinical Trial Unit)
• Have a valid MedDRA license
• Register user data in EudraVigilance
• Register product in the Eudravigilance product dictionary, XEVMPD (only if the
product isn’t already registered)

MedDRA = Medical Dictionary for Drug Regulatory Affairs

XEVMPD = Extended EudraVigilance Medicinal Product Dictionary
Current SUSAR reporting option (Norway, only)

Current* option in Norway for non-commercial sponsors:

• SUSARs can be reported on paper using CIOMS form (Eudract number
must be added to form)
• Submit form by e-mail to post@legemiddelverket.no

* As per 4 February 2021

Urgent Safety Measures

• Unexpected events that might materially influence the benefit-risk

assessment of the IMP or that would lead to changes in the administration
of an IMP or in overall conduct of a clinical trial must be notified to the
competent authorities.
• Where an unexpected event is likely to seriously affect the benefit-risk
balance, the sponsor and the investigator shall take appropriate urgent
safety measures to protect the subjects.
• Any urgent safety measures taken must be reported to the competent
authorities as soon as possible after measures have been taken.
Development Safety Update Report (DSUR)

• “a comprehensive, thoughtful annual review and evaluation of pertinent

safety information collected during the reporting period related to a drug
under investigation”

• If feasible, one single DSUR with data pertinent to all dosage forms and
strengths, all indications, and all patient populations under study with the
investigational drug, should be written. However, the sponsor is
responsible for including at least safety data from the clinical trial(s) for
which the organsiation is responsible.

ICH guideline E2F on development safety update report

DSUR

• Annual report covering all participating countries

• The first approval date of the clinical trial in any country (called the
Development International Birth Date (DIBD)) defines when the report is
due. (If the first approval date of any clinical trial is not known, it is ok to use the approval date of
the applicable clinical trial as “DIBD”.)
• The reporting period is 12 months from the DIBD.
• The submission deadline is 60 days after the DIBD.
• The DSUR should be written in English for possible use in any country.
DSUR submission

Under 2001/20/EC:
• Submitted to competent authorities and ethics committees via their regular
reporting system (e-mail, database systems)
• Some ethics committees don’t want DSURs (example: Norwegian REK)

Under 536/2014:
• Submitted via the EU Portal
Alternative Annual Safety Report (Norway, only)

Current* option in Norway for non-commercial sponsors:

• If the study is ongoing in Norway, only, a simpler annual report form can be
submitted to the Norwegian Medicines Agency instead of the DSUR.

• Årsrapportskjema til Legemiddelverket

• Submit form by e-mail to post@legemiddelverket.no

* As per 04 February 2021

Investigator’s Brochure (IB)

• A compilation of the clinical and nonclinical data on the investigational

product(s) that are relevant to the study of the product(s) in human
subjects.

• Purpose: information to facilitate study staff’s understanding of the

rationale for, and their compliance with, many key features of the protocol,
such as the dose, dose frequency/interval, methods of administration and
safety monitoring procedures.

• Must be reviewed annually and revised as necessary

Good luck with the safety reporting
in your study!