PHARMACOVIGILANCE WORKSHOP

INTRODUCTION

BERN
27 & 28 January 2009

R. Stoller
Swissmedic Division Safety of Medicines
 PV WORKSHOP - INTRODUCTION

A Introduction to PV
B Definitions
C The Swiss PV Network
D Duty of information
- the rules ( a short repetition of the
morning presentation)
- good case management practice (GCMP)
A Pharmacovigilance – examples
introduction to PV
B Definitions
C The Swiss PV Network
D Duty of information
 PHARMACOVIGILANCE (PV) is

„finding the needle in the haystack“

„the science and activities relating to the detection,

understanding and prevention of adverse effects and
any other drug related problem“
WHO Technical Report No 498 (1972)

„bad news and cost“

(anonymous lady, out of her every-day-experience)
 ADRs...

And any other drug related problem:

medication errors
quality defects
shortage of supply
abuse, misuse, intoxications
illicit drugs, counterfeits...
and.....
 PV
THE PROCEDURE
PHARMACO risk VIGILANCE
minimising
action & risk
communication
signal (confirmed)

signal (suspected)

case series

individual case safety report (ICSR)

or other report on product problem
 PHARMACOVIGILANCE

EFFECTS UNKONWN AT AUTH0RISATION

unexpected
frequency < 1 -2 %
children, elderly,
pregnant women...
due to comorbidity
due to comedication: interactions
due to other indication
other dose, long term use
 DETECTING SIGNALS

My dear Watson, you see, but you do not observe...

Sir Arthur Conan Doyle. A Scandal in Bohemia.
 RISK
CONSTELLATION
 DRUG -
INTRINSIC PROPERTIES & QUALITY

SIGNAL

PATIENT RISK FACTORS

DRUG USAGE
& COMORBIDITY
 SIGNAL =

• suspected new drug risk

• change in nature of known ADR
– outcome (seriousness)
– severity (intensity of symptoms)
– specificity or
– frequency or ....
• new risk factor
• drug utilisation or prescribing problem
 Risk factors

An ADR appearing to be very rare in the general

population may be frequent in selected patients: identify
risk factors / contraindications. This can save the patient
(and the drug).
Example:
NSAID induced renal failure
in general population vs. nephrology patients
 Drug utilisation or
prescribing problems

These account for a relevant part of ADRs and

constitute an important public health problem,
in industrialised as well as in developing countries.

In the Lausanne study e.g.*, more than half of all

registered ADRs were judged to have been preventable
to an extent of more than 50 %…

* Livio F. et al. Lausanne: Institut universitaire de médecine sociale et préventive, 1998

(Raisons de Santé 23)
 DETERMINANTS OF SIGNAL -> CONTENT OF ICSR (I)

• HOW UNEXPECTED* COMMENT ON PRODUCT INFORMATION

• HOW SERIOUS DOCUMENT OUTCOME
• HOW SEVERE USE ADR TERMS SHOWING INTENSITY
(e.g. hepatitis with encephalopathy,
prothrombin time prolonged & jaundice)
QUANTIFY, DESCRIBE IN NARRATIVE
(lab., ADR duration, all relevant signs &
symptoms)
• RISK FACTORS RELEVANT COMORBIDITY /
PREDISPOSING FACTORS
SUSP. DRUGS: DOSE & DURATION
COMEDICATION
**Unexpected
Unexpected(ICH(ICHE2D)
E2D)--an
anADR
ADRwhose
whosenature,
nature,specificity
specificityor
oroutcome
outcomeisisnot
not
consistent
consistentwith
withthetheterm
termor
ordescription
descriptionused
usedininthe
thereference
referencedocument
document
DETERMINANTS OF SIGNAL -> CONTENT OF ICSR (II)
• NATURE AND REFLECT DIFFERING PATTERN
SPECIFICITY BY CHOICE OF ADR-TERMS
DESCRIBE IN NARRATIVE
(e.g. symptoms, latency, dose,...)
• CAUSALITY TEMPORAL RELATIONSHIP
ONSET-LATENCY
DECHALLENGE (DESCRIBE!)
RECHALLENGE
NON-DRUG CAUSES
• QUALITY OF
DOCUMENTATION IS A DIAGNOSIS POSSIBLE?
MISSING ELEMENTS
PENDING REQUESTS FOR MORE
INFORMATION
• DRUG USAGE (CONTRA-) INDICATION(S),
Dose, …..
 IMPUTABILITY

ADRs are drug-induced diseases and are not principally

different from other diseases with regard to diagnostic
procedures and differential diagnosis.

disease

drug
SWISSMEDIC IMPUTABILITY: KNOWN REACTION
(mentioned in Meyler‘s SED, AHFS, Martindale,
mdx drug information or Product Information)
CERTAIN temporal relationship
improvement after dechallenge*
recurrence after rechallenge
(or other proof of drug cause)
PROBABLE temporal relationship
improvement after dechallenge*
no other cause evident
POSSIBLE temporal relationship
other cause possible
UNLIKELY any assessable reaction that does
not fulfil the above conditions
UNCLASSIFIABLE not assessable due to lack of data
* improvement after dechallenge only taken into consideration if
applicable to reaction; e.g.: not applicable in liver cirrhosis
 SWISSMEDIC IMPUTABILITY:
NEW REACTION

The imputability, in a first step determined as for

known reactions, is then graded 1 (2) levels lower:

certain probable; probable possible;

possible unlikely - but remains
possible in suggestive cases

of course unlikely and

unclassifiable remain unchanged
 SWISSMEDIC IMPUTABILITY
(non-interacting drugs)

• ADR „CERTAIN“
– one drug „certain“, all others „unlikely“
• ADR „PROBABLE“
– one drug „probable“, all others „possible or „unlikely“
• ADR „POSSIBLE“
– one or more drugs possible, all others unlikely
A Pharmacovigilance – examples
introduction
B Definitions
C The Swiss PV Network
D Duty of information
 ADVERSE EVENT (AE)

Any untoward medical occurrence in a patient administered a

medicinal product and which does not necessarily have to
have a causal relationship with this treatment.
...can therefore be any unfavourable and unintended sign
(e.g., an abnormal lab. finding), symptom, or disease
temporally associated with the use of a medicinal product,
whether or not considered related to this medicinal product.

ICH guideline E2D

 ADVERSE DRUG REACTION (ADR)
=
"A response to a drug which is noxious and
unintended, and which occurs at doses normally
used in man for the prophylaxis, diagnosis, or
therapy of disease, or for the modification of
physiological function.“
WHO Technical Report No 498 (1972)

Comments (ICH guideline E2D)

...response means that a causal relationship is at least a reasonable possibility*.
A reaction, in contrast to an event, is characterised by the fact, that a causal relationship is suspected.
For regulatory reporting purposes, if an event is spontaneously reported, even if the relationship is
unknown or unstated, it meets the definition of an ADR.
 SERIOUS AE or ADR

Any untoward medical occurrence that at any dose

• results in death
• is life-treatening
• requires / prolongs inpatient hospitalisation
• results in persistent or significant disability / incapacity
• is a congenital anomaly or birth defect
• is a medically important event or reaction

ICH guideline E2D

 SERIOUS AE or ADR (cont.)
medically important“
„Medical and scientific judgement should be exercised in deciding
whether expedited reporting is appropriate in other situations, such as
important medical events that may not be immediately life-threatening
or result in death or hospitalisation but may jeopardise the patient or
may require intervention to prevent one of the other outcomes
listed in the definition above. These should also usually be con-
sidered serious.
Examples of such events are intensive treatment in an emergency room
or at home for allergic bronchospasm; blood dyscrasias or convulsions
hat do not result in hospitalisation; or development of drug dependence
or drug abuse.
ICH guidelines E2D & E2A
 „SERIOUS“ versus „SEVERE“

An AE or ADR is classified as „serious“ depending on it‘s

consequences for the patient and it‘s outcome.

The term „severe“ relates to the intensity of signs or symptoms

e.g.
fever > 390 < -- > subfebrile temperature
thrombocytopenia 3 G / l < -- > tc.penia 90 G / l
rash involving whole body < -- > isolated eruptions
on forearms

ICH guideline E2A

 UNEXPECTED ADR

An ADR whose nature, severity, specificity, or outcome is

not consistent with the term or description used
- in the local / regional product labeling (e.g. Package
Insert or Summary of Product Characteristics)
-> UNLABELLED ADR post-approval, ICH guideline E2D

- in the applicable product information (e.g. Investigtor‘s

Brochure for an unapproved investigational medicinal product)
-> UNEXPECTED ADR pre-approval, ICH guideline E2A
 UNLISTED ADR

The term „LISTEDNESS“ is not applicable to expedited

reporting but should be used to characterise the ADR
according to the Company Core Safety Information (CCSI).
(comment: in the context of PSURs)
..
ICH guideline E2D
also refer to ICH guideline E2C
 MINIMUM CRITERIA for REPORTING

1. identifiable reporter
2. identifiable patient
3. ADR
4. suspected product

The term identifiable in this context refers to the verification ot

the existence of a patient and a reporter.
One or more of the following should automatically qualify a
patient as identifiable: age (or age category), gender,
initials, date of birth, name or pat. identification No...

iCH guideline E2D

A Pharmacovigilance – examples
introduction
B Definitions
C The Swiss PV Network
D Duty of information
A Pharmacovigilance – examples
introduction
B Definitions
C The Swiss PV Network
D Duty of information
 WHO COLLABORATING
CENTRE

INDUSTRY

ZH
STIZ 2

GE
PHARMACOVIGILANCE BS
SWISSMEDIC

VD
STIS 1 BE
BE
TI

1 STIS = Swiss Teratogen Information Service

2 STIZ = Schweizerisches Toxikologisches Informationszentrum
 THE PHARMACOVIGILANCE FLOW-SHEET: DO UT DES
WHO CENTRE for international database
FOREIGN PV CENTRES INTERNATIONAL DRUG signals
MONITORING
int. data (online) int.
signals
Swiss database
SWISS PV CENTRE signals
swiss & int. reports safety action
swiss & int.
Signals / actions
evaluate (lit.-search
SWISS REGIONAL PV comment
comment and advice CENTRE data entry

change therapy HEALTH CARE report ADR (new

treat ADR PROFESSIONAL form)
prevent further ADRs
PATIENT report ADR
 Uppsala Monitoring
Centre (WHO) Identical
time-frames

Swissmedic
authorities companies
PV Centre
contract new serious, clusters

Regional PV Centre
duty to report new serious
Art. 59 HMG,
Art. 35,36,38 VAM
healthcare professionals
right to report
Art. 59 HMG
patients, consumers
 therapeutic products
veterinary
medicines (TAM)
TAM-vigilance medical devices
medicines
medical devices
human medicines (MEP)
Pharmacovigilance materiovigilance
(„synthetic“, biotechno-
logical drugs,
complementary drugs and labile blood
herbals, biologics (vaccines, products
stable blood products..) hemovigilance

WE ARE HERE
 - new organisation after July 1st 2007
Market Surveillance
(K. Mathys)

Safety of Medicines
(R.Stoller)

Vigilance
risk management: (Pia Caduff):

PV planning pharmaco-
urgent safety issues hemo- vigilance
including DHPL
veterinary
PSURs
4500 No of ADR reports Swissmedic Pharmacovigilance Centre
4195
4000
Regional PV Centres 3902

3500 Companies
3326 3313
SDMC
3000 3071

Total 2853

2500
2361

2000 2001 2007

1500 1582

2339
982
1000 1145
1852 1830 1789
1972 1930
1856
1714
632
1496 1524
1084 1219
1166 1139
500
569
455 495 450 424 438
111
0 1998
19981999 1999
2000
2000
2001
2001
2002 2003
20022004 2003
2005
2004
2006
2005
2007
2006 2007
 N
ew

0
100
200
300
400
500
600
700
800
900
Ze
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Average during year 2002 - 2006

ng
ap
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ai
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Active ADR-reports in Vigibase /1 million inhabitants

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A Pharmacovigilance – examples
introduction
B Definitions
C The Swiss PV Network
D Duty to report - the rules
 Companies’ duty to report

1. ad hoc -> relevant safety signals

2. continuous -> Single case safety reports (ICSR)
(only if originating from Switzerland)
3. periodic / in context of conditional approval
-> PSURs
or yearly summary on safety for clinical trials
(see documentation)
N.B. The rules for all three types of reporting can be modified
in the context of specific PV plans according to ICH E2E,
in force in Switzerland from Jan 1st 2007.
 originating outside originating from
clinical trial notified by clinical trial notified by
Swissmedic- Swissmedic
ad hoc safety signals safety signals

individual serious serious-related-

case or unexpected (SUSADRs)
safety unlabelled originating from
reports originating from Switzerland („domestic“)
(ICSR) Switzerland („domestic“)

periodic PSURs yearly safety update

 DUTY TO risk REPORT
minim. • risk requiring immediate
finding / evaluation action
impacting on basis
action • significant potential
of assessment risk, in evaluation for harm
Art. 59 2 HMG for safety action, • smaller potential
Art. 35, 16 VAM (domestic or international) for harm:
• non-urgent
Art. 58 3 variation
59 1-3
LPT35 1-2
signal (suspected)
VAM

individual case safety reports

(only domestic): serious, cluster or unexpected
Companies’ duty to report

STARTS:
when company applies for authorisation and
ENDS
at the expiry date of the last lot distributed in Switzerland

(clinical trials: duty to report starts at notification)

Contacts for companies (I)
Vigilance Unit :
• ICSR
• domestic
• on human medicines
(including labile blood products)
• authorised / running application OR
• originating from clinical trials notified by Swissmedic
medicines = synthetic, biotechnological drugs, vaccines &
blood products, complementary & herbal drugs and...
 What to whom?
Market Surveillance Authorisation
(K. Mathys) (U. E. Kopp)

Safety of medicines Case Management

Vigilance „ GESUCHE“new
(A. Schneider):
Risk Management: drug applications,
variations
pharmaco-
- PV planning
hemo- - urgent safety issues / HPC
veterinary - PSURs
Swiss
vigilance
ICSR
Contacts for companies (II)
address:
Swissmedic
Vigilance Unit
Hallerstr. 7
3000 Bern 9
Tel. 031 322 03 52
Fax 031 322 04 18
vigilance@swissmedic.ch
Contacts for companies (III)
send:
• nationally / internationally identified safety signals of
authorised medicines
to the Division Case Management (CM)
• quality defects
to the Division Market Monitoring of Medicines (MKA)
• nationally / internationally identified safety signals occurring
in the context of a Swissmedic-notified clinical trial
to the Division Clinical Trials (KLV)
Contacts for Swissmedic
- outside clinical trials notified by Swissmedic
the Swiss marketing authorisation holder (mah)

- in the context of clinical trials notified by

Swissmedic
the sponsor

Mah / sponsor are responsible to coordinate

reporting by international CROs.
Swiss ICSR outside the context of clinical trials
notified by Swissmedic-

What and when to report? (I)

(N.B. days = calendar days) < 15 days
• serious ADRs
(„serious“ according to ICH E2D)
immediately,
– death
<< 15 days
– life-threatening (several steps)
– requires / prolongs inpatient hospitalisation
– persistent or significant disability / incapacity
– congenital anomaly or birth defect
– “medically important”
Swiss ICSR outside the context of clinical trials
CH-Meldungen ausserhalb Swissmedic-
notified by Swissmedic
notifizierter klinischer Versuche
immediately,
<< 15 days
What and when to report? (II)
• unexpected increase in frequency
– of labelled or
– unlabelled ADR
– serious misuse or intoxications if increasing in frequency

• non-serious-unlabelled 60 days
(= ADRs not / inadequately mentionned in the last approved
Swiss product information
Swiss ICSR outside the context of clinical trials
notified by Swissmedic
How to report? (I)
• as ICSR
• reporting form: CIOMS-form, English texts O.K.)
With all relevant available information:
- ADR description, chronology, outcome
- evaluation / comment on Swiss labelling
• if possible electronic transmission
- pdf-text, on diskette or by e-mail,
later: E2B-format according to ICH
Swiss ICSR outside the context of clinical trials
notified by Swissmedic
How to report? (I)
• Covering letter / e-mail
if missing in ADR form:
- evaluation of the problem in context of present data
- ADR labelled (Swiss product information)? How?
- planned investigations and risk minimizing action
- administrative data: Please refer to Swiss-
o in all later
company ADR N o medic ADR N
initial report / follow-up correspondence!
possible duplicate report - when, by whom, to whom?
Swiss ICSR outside the context of clinical
trials notified by Swissmedic

ADR mentioned in product information – and how? (I)

In cover letter if not discussed in CIOMS form:

– ADR labelled - yes / no?

• N.B.: labelled = consistent with text of prod. info,
but term needs not be specified verbatim
• cave: citation of an ADR in comparative adverse event
lists # labelled, unless clearly declared as related
to the product
ADR mentioned in product information – and how? (II)
– If the coded ADRs are not mentioned verbatim in the
respective chapter of the last product information
approved by Swissmedic,
provide a short citation of related ADRs
or refer to corresponding organ class
the reference is the ADR section,
• in case of interactions: also consider the respective
chapter
• in case of overdose refer to this section
 Follow-up reports
REDUCE, REFINE, REPLACE…
• limit No and frequency
• always indicate date of follow-up information
• clearly state / highlight what has been changed in
– structured data fields and
– narrative,
- e.g.
“20 June 2006 – additional information received from
reporter: drug name changed from unknown to
Voltaren; strength (50 mg), dose (3 tablets daily)
completed, outcome changed from unknown to
recovered.”
Relevant safety signals (outside notif. clin. trials)

What and when to report? (I)

• Risks insufficiently known requiring preventive action

(including publication / information) or being investigated
regarding such consequences („confirmed signals“)
5 days
- urgent need for risk minimizing action
without delay
- significant potential for harm << 15 days
- smaller potential for harm
6 months
Relevant safety signals. (outs notified clin.trials)

immediately
What and when to report? (II)
<< 15 days
• unexpected increase in frequency
• of labelled or unlabelled ADRs
• serious misuse or intoxications if increasing in frequency
• quality defects (involving batches in Switzerland)

class I: 24 h
• shortage of supply class II: 3 days
class III: 15 days
Relevant safety signals (outs. notified clin.trials)

How to report?
• no isolated ICSR, but a concise critical evaluation of the
suspected new risk, including estimates of it´s incidence.
Add original references as necessary.
• planned further investigations and preventive measures
• Swissmedic authorisation No of involved products
To whom?
• to the Division Case Management
Clinical trials notified by Swissmedic

ICSR: What and how to report? < 7 days

• lethal or life-threatening ADRs

originating in Switzerland < 15 days
if serious - related - unexpected *
• other serious-related-unexpected * ADRs
originating in Switzerland
(cumulative: all 3 criteria must be fulfilled!)
• no isolated ICSR from foreign countries!

* Sponsors: please coordinate reporting with international

CROs!
Clinical trials notified by Swissmedic
ICSRs: How to report (I) ?
• covering e-mail / letter (if missing in reporting form):
- initial or follow-up
- why „unexpected“ (short citation of investigator´s
brochure, IB)?
- causality
- Swissmedic trial No (notification No)
- Consequences / investigations
• ADR report: CIOMS-form with all available relevant data
- if possible in electronic form (CIOMS-form as pdf-text)
- if paper-printout: please in 2 copies
Clinical trials notified by Swissmedic
Notifizierte klinische Versuche
ICSRs: How to report (II) ?
why „unexpected“?
- what does the investigator´s brochure say?
in cover letter / e-mail if missing in report form:
-> short citation of IB referring to related effects or the
respective organ class, as required for ICSR outside a
context of clinical trials notified by Swissmedic
Clinical trials notified by Swissmedic
Notifizierte klinische Versuche
Once a year to
GCP division
• safety summary
Concise, critical summary on the ADR profile of the
investigated drug, with listings of at least the reportable
ADRs:
– all deaths and life-threatening ADR
internationally,
if related - unexpected
– serious-related-unexpected ADRs internationally
Company‘s reporting system

The manufacturer or distributor of therapeutic products must

establish a reporting system (Art. 591 LTP)
• Art. 39 VAM
1 collects all reportable informations centrally
2 evaluates them without delay and takes risk
minimizing action
3 transmits them as ordered,
answers questions of the institute (I.e. Swissmedic)
4 assigns a qualified person, competent in the field
Qualified person responsible for PV

• art. 7 3f Ordinance on Establishment Licences

(ELO, AMBV, OMED).
Anyone who applies for an authorisation to trade wholesale
or import ready-to-use medicinal products and who in
addition wishes to release them, must also ensure …
• qualified person responsible for pharmacovigilance, who…
- is in charge of reporting ADRs in accordance with Art.
35
and 39 VAM,
- has the specialist knowledge
- needs not to be on the staff of the company
- has responsibilities put down in writing
• residence in Switzerland is no longer required!
12 mistakes (I)
• company informs late on relevant action in foreign country
• fails to report unexpected cluster of ADRs
• doesn't send report on relevant safety signal separately
and clearly recognizable as such, but e.g. as part of a PSUR
or when applying for a routine change of the product
information
• sends isolated ICSR from foreign countries without
providing signal dossier
• sends isolated ICSR relating to Swissmedic notified clinical
trial which does NOT refer to a serious-related-unexpected
ADR (SUSADR) originating in Switzerland
12 mistakes (II)

• sends reports deficient in content:

chronology, differential diagnoses, outcome ...
• doesn't report on CIOMS-form
• fails to cite product information / IB if coded ADR not
mentioned verbatim in the reference document
• omits to check Swissmedic‘s confirmation of receipt
• doesn't refer to Swissmedic ADR No in follow-up
correspondence
• doesn't‘t refer to Swissmedic trial No (report from study)
• neglects coordination of ADR reporting with international
CROs during clinical trials
 REFERENCES

ICH International Conference on Harmonisation - Guidelines

www.ich.org
E2A: Clinical Safety Data Management : Definitions and Standards for Expedited Reporting
E2C: Clinical Safety Data Management : Periodic Safety Update Reports for Marketed
DrugsE2D: Post-Approval Safety Data Management: Definitions and Standards for Expedited
Reporting
E2E: Pharmacovigilance Planning
CIOMS Council for International Organisations of Medical Sciences
www.cioms.ch
Current Challenges in Pharmacovigilance: Pragmatic Approaches
(Report of CIOMS Working Group V)
U.S. FDA guidances
Good PV Practice and PE assessment
Pre-Marketing Risk assessment
Risk Minimisation Action Plans