3 Pharmacovigilance Introduction

PHARMACOVIGILANCE WORKSHOPINTRODUCTION

BERN27 & 28 January 2009

R. StollerSwissmedic Division Safety of Medicines

PV WORKSHOP - INTRODUCTION

A Introduction to PVB DefinitionsC The Swiss PV NetworkD Duty of information

- the rules ( a short repetition of the morning presentation)

- good case management practice (GCMP)

A Pharmacovigilance – examplesintroduction to PV

B DefinitionsC The Swiss PV NetworkD 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 errorsquality defects

shortage of supplyabuse, misuse, intoxications

illicit drugs, counterfeits...and.....

PVTHE PROCEDURE

individual case safety report (ICSR) or other report on product problem

case series

signal (suspected)

signal (confirmed)

risk minimising

action & riskcommunication

PHARMACO VIGILANCE

EFFECTS UNKONWN AT AUTH0RISATION

unexpectedfrequency < 1 -2 %children, elderly,

pregnant women...due to comorbiditydue to comedication: interactionsdue to other indicationother dose, long term use

PHARMACOVIGILANCE

My dear Watson, you see, but you do not observe...Sir Arthur Conan Doyle. A Scandal in Bohemia.

DETECTING SIGNALS

RISK CONSTELLATION

DRUG -INTRINSIC PROPERTIES & QUALITY

PATIENT RISK FACTORS & COMORBIDITY DRUG USAGE

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

SIGNAL =

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*• HOW SERIOUS• HOW SEVERE

• RISK FACTORS

COMMENT ON PRODUCT INFORMATIONDOCUMENT OUTCOMEUSE ADR TERMS SHOWING INTENSITY

(e.g. hepatitis with encephalopathy, prothrombin time prolonged & jaundice)

QUANTIFY, DESCRIBE IN NARRATIVE(lab., ADR duration, all relevant signs & symptoms)

RELEVANT COMORBIDITY / PREDISPOSING FACTORSSUSP. DRUGS: DOSE & DURATIONCOMEDICATION

* Unexpected (ICH E2D) - an ADR whose nature, specificity or outcome is not consistent with the term or description used in the reference document

* Unexpected (ICH E2D) - an ADR whose nature, specificity or outcome is not consistent with the term or description used in the reference document

• NATURE AND SPECIFICITY

• CAUSALITY

• QUALITY OF DOCUMENTATION

• DRUG USAGE

REFLECT DIFFERING PATTERNBY CHOICE OF ADR-TERMSDESCRIBE IN NARRATIVE(e.g. symptoms, latency, dose,...)TEMPORAL RELATIONSHIP ONSET-LATENCYDECHALLENGE (DESCRIBE!)RECHALLENGENON-DRUG CAUSES

IS A DIAGNOSIS POSSIBLE?MISSING ELEMENTSPENDING REQUESTS FOR MOREINFORMATION(CONTRA-) INDICATION(S), Dose, …..

DETERMINANTS OF SIGNAL -> CONTENT OF ICSR (II)

IMPUTABILITY

ADRs are drug-induced diseases and are not principallydifferent from other diseases with regard to diagnostic procedures and differential diagnosis.

drug

disease

SWISSMEDIC IMPUTABILITY: KNOWN REACTION(mentioned in Meyler‘s SED, AHFS, Martindale,mdx drug information or Product Information)

CERTAIN temporal relationshipimprovement after dechallenge*recurrence after rechallenge(or other proof of drug cause)

PROBABLE temporal relationship improvement after dechallenge*no other cause evident

POSSIBLE temporal relationshipother 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 forknown 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


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

medically important“

„Medical and scientific judgement should be exercised in decidingwhether expedited reporting is appropriate in other situations, such asimportant medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise the patient ormay require intervention to prevent one of the other outcomeslisted in the definition above. These should also usually be con-sidered serious.Examples of such events are intensive treatment in an emergency roomor 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 AE or ADR (cont.)

„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 symptomse.g. fever > 390 < -- > subfebrile temperaturethrombocytopenia 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 reporter2. identifiable patient3. ADR4. suspected product

The term identifiable in this context refers to the verification otthe 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





WHO COLLABORATING CENTRE

PHARMACOVIGILANCE SWISSMEDIC

INDUSTRY

BS

BEBE

VDSTIS 1

GE

1 STIS = Swiss Teratogen Information Service2 STIZ = Schweizerisches Toxikologisches Informationszentrum

ZHSTIZ 2

TI

THE PHARMACOVIGILANCE FLOW-SHEET: DO UT DESWHO CENTRE for

INTERNATIONAL DRUG MONITORING

SWISS PV CENTRE

SWISS REGIONAL PV CENTRE

HEALTH CARE PROFESSIONAL

PATIENT report ADR

report ADR (newform)

evaluate (lit.-searchcommentdata entry

Swiss databasesignalssafety action

international databasesignalsFOREIGN PV CENTRES

int. data (online) int. signals

swiss & int. reportsswiss & int.

Signals / actions

change therapy treat ADR prevent further ADRs

comment and advice

patients, consumers

healthcare professionals

Regional PV Centre

SwissmedicPV Centre

Uppsala Monitoring Centre (WHO)

right to report Art. 59 HMG

duty to report Art. 59 HMG, Art. 35,36,38 VAM

contract

companiesauthorities

new serious

new serious, clusters

Identical time-frames

therapeutic products

human medicinesPharmacovigilance

(„synthetic“, biotechno-logical drugs,

complementary drugs and herbals, biologics (vaccines,

stable blood products..)

medical devices(MEP)

materiovigilance

veterinary medicines (TAM)

TAM-vigilance

labile blood products

hemovigilance

medicines medical devices

WE ARE HERE

- new organisation after July 1st 2007Market Surveillance

(K. Mathys)

Safety of Medicines(R.Stoller)

risk management: Vigilance(Pia Caduff):

pharmaco-

hemovigilance

veterinary

PV planning

urgent safety issuesincluding DHPL

PSURs

455 450 424

1166

1714 1852 1830 17891972 1856

632

982 1145

10841139 1219

1496 1524

1930

2339

3326 3313

3902

4195

111

569495 438

1582

2001 2007

2361

2853

3071

0

500

1000

1500

2000

2500

3000

3500

4000

4500

CompaniesSDMC

Total

Regional PV Centres

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

No of ADR reports Swissmedic Pharmacovigilance Centre

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Active ADR-reports in Vigibase /1 million inhabitants Average during year 2002 - 2006

0

100

200

300

400

500

600

700

800

900

New Zea

land

Netherl

ands

Australi

aCan

ada

United Stat

esSwitz

erlan

dSwed

enNorw

ayIre

land

France

United K

ingdomDen

mark

CubaSingap

oreThail

and

Finland

German

ySpainIce

land

Croati

a

CH 2006: 540 / Mio Einw.

CH: Rang 6


B DefinitionsC The Swiss PV NetworkD 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.

serious-related-unexpected (SUSADRs)originating from Switzerland („domestic“)

serious or unlabelled originating from Switzerland („domestic“)

individual case safety reports (ICSR)

yearly safety updatePSURsperiodic

safety signalssafety signalsad hoc

originating from clinical trial notified bySwissmedic

originating outside clinical trial notified bySwissmedic-

• smaller potential for harm:

• significant potential for harm

• non-urgent variation

signal (suspected)

individual case safety reports (only domestic): serious, cluster or unexpected

risk, in evaluation for safety action,

(domestic or international)

riskminim. action

Art. 58 359 1-3

LPT35 1-2

VAM

• risk requiring immediate action

DUTY TO REPORTDUTY TO REPORTfinding / evaluation impacting on basis of assessmentArt. 59 2 HMGArt. 35, 16 VAM

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

(K. Mathys)

Safety of medicines

Risk Management:Vigilance(A. Schneider):

pharmaco-hemo-veterinaryvigilance

Authorisation(U. E. Kopp)

Case Management

- PV planning- urgent safety issues / HPC- PSURs

„ GESUCHE“newdrug applications, variations

Swiss ICSR

Contacts for companies (II)address:SwissmedicVigilance UnitHallerstr. 73000 Bern 9

Tel. 031 322 03 52Fax 031 322 04 18

[email protected]

Contacts for companies (III) send:send:• nationally / internationally identified safety signals of

authorised medicines to the Division Case Management (CM)

• quality defectsto the Division Market Monitoring of Medicines (MKA)

• nationally / internationally identified safety signals occurringin the context of a Swissmedic-notified clinical trial

to the Division Clinical Trials (KLV)

Contacts for Swissmedic

- outside clinical trials notified by Swissmedicthe Swiss marketing authorisation holder (mah)

- in the context of clinical trials notified bySwissmedicthe 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)

• serious ADRs(„serious“ according to ICH E2D)– death– life-threatening– requires / prolongs inpatient hospitalisation– persistent or significant disability / incapacity– congenital anomaly or birth defect– “medically important”

immediately, << 15 days

(several steps)

< 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 (= ADRs not / inadequately mentionned in the last approved Swiss product information

CHCH--Meldungen ausserhalbMeldungen ausserhalb SwissmedicSwissmedic--notifizierter klinischer Versuche notifizierter klinischer Versuche

Swiss ICSR outside the context of clinical trials notified by Swissmedic

immediately, << 15 days

60 days

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


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:

company ADR No

initial report / follow-up possible duplicate report - when, by whom, to whom?


Please refer to Swiss-medic ADR No in all later correspondence!

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

Swiss ICSR outside the context of clinicaltrials notified by Swissmedic

ADR mentioned in product information – and how? (II)– If the coded ADRs are not mentioned verbatim in the

respective chapter of the last product informationapproved by Swissmedic,provide a short citation of related ADRsor refer to corresponding organ classthe reference is the ADR section, • in case of interactions: also consider the respective

chapter• in case of overdose refer to this section

• 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.”

Follow-up reportsREDUCE, REFINE, REPLACE…

• Risks insufficiently known requiring preventive action(including publication / information) or being investigatedregarding such consequences („confirmed signals“)

- urgent need for risk minimizing action

- significant potential for harm

- smaller potential for harm

Relevant safety signals (outside notif. clin. trials)

What and when to report? (I)

without delay << 15 days

5 days

6 months

• unexpected increase in frequency• of labelled or unlabelled ADRs• serious misuse or intoxications if increasing in frequency

• quality defects (involving batches in Switzerland)

• shortage of supply

immediately << 15 days

class I: 24 hclass II: 3 days class III: 15 days

Relevant safety signals. . (outs notified clin..trials))

What and when to report? (II)

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

Relevant safety signals (outs. notified clin.trials)

Clinical trials notified by Swissmedic

ICSR: What and how to report?

• lethal or life-threatening ADRsoriginating in Switzerlandif serious - related - unexpected *

• other serious-related-unexpected * ADRsoriginating in Switzerland(cumulative: all 3 criteria must be fulfilled!)

• no isolated ICSR from foreign countries!

* Sponsors: please coordinate reporting with international CROs!

< 7 days

< 15 days

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

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

NotifizierteNotifizierte klinische Versucheklinische VersucheClinical trials notified by Swissmedic

• safety summaryConcise, critical summary on the ADR profile of the investigated drug, with listings of at least the reportableADRs:– all deaths and life-threatening ADR

internationally, if related - unexpected

– serious-related-unexpected ADRs internationally

Notifizierte klinische VersucheNotifizierte klinische VersucheClinical trials notified by Swissmedic

Once a year to GCP division

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 action3 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

• 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

12 mistakes (II)

REFERENCES

ICH International Conference on Harmonisation - Guidelineswww.ich.org

E2A: Clinical Safety Data Management : Definitions and Standards for Expedited ReportingE2C: Clinical Safety Data Management : Periodic Safety Update Reports for Marketed DrugsE2D: Post-Approval Safety Data Management: Definitions and Standards for Expedited ReportingE2E: Pharmacovigilance PlanningCIOMS Council for International Organisations of Medical Sciences

www.cioms.chCurrent Challenges in Pharmacovigilance: Pragmatic Approaches(Report of CIOMS Working Group V)U.S. FDA guidancesGood PV Practice and PE assessmentPre-Marketing Risk assessmentRisk Minimisation Action Plans

Documents

3 Pharmacovigilance Introduction