pharmacoepidemiology used for · pdf filepharmacoepidemiology used for pharmacovigilance...

Châtenay-Malabry January 2013 1

Pharmacoepidemiology

used

for pharmacovigilance

Stéphanie Tcherny-Lessenot,

MD MSc MPHPharmacoepidemiologistGlobal

Pharmacovigilance & Epidemiology,

Sanofi R&D

23

January 2013

2

Objectives

●Objectives of the training are to:●

Provide

some

background on Pharmacoepidemiology

(PE)

●

Provide

the current

European

Regulatory

context

relative to Pharmacovigilance (PV)

●

Connect


to Pharmacovigilance

3

Agenda

●

Background on pharmacoepidemiology●

Current

European

PV regulations

●

Place of pharmacoepidemiology

in pharmacovigilance●

Illustrative cases

●

Conclusion

4

What is pharmacoepidemiology

(PE)?

Genetic Epidemiology Pharmacoepidemiology

Cardiovascular Epidemiology

Cancer Epidemiology

Environmental EpidemiologyNutrition

Epidemiology

Epidemiology

is the study of the distribution and determinants of diseases in populations


is the study of the use of and the effects of drugs in large numbers of people

Ref: Textbook of Pharmacoepidemiology

Brian L. Strom and Stephen E. Kimmel-

John Wiley & Sons , Ltd

5

What are Epidemiological Studies?

= Observational Studies= Non-interventional Studies= No treatment assignment by a third party (decision only by patient and physician)= In real life setting

●

Main types●

Prospective

new data collection●

Retrospective

use of existing data●

Cross-sectional

one shot data

●

Epidemiologic study designs:●

Cohort

study●

(nested) Case-control

study●

Case-crossover study●

…●

Main data sources●

Field studies:

specifically performed to address specific needs, and study

participants recruited

for the purpose

of the study●

Databases studies: Study

subjects

are identified

in the existing

databases

where

data are usually

collected

for administrative purpose; thus, not specific

to the study

6

Which Pharmaco-epidemiologic study designs?

Case report

Case series (uncontrolled, open)

Ecologic (analyses of secular

trends)

Descriptive (non-comparative)

Cross-sectional

Cohort

Non-experimental (observational)

RCT

Experimental

Analytic (comparative)

Case-control

Study design

** Interventional** Survey

**

*** Randomized Control Trial

***

7

+ Rx+ RxOutcome?Outcome?

ExposureExposure

Main designs in (pharmaco-)epidemiology

OutcomeOutcomeCase-controlExposure?Exposure?

Cross-sectional

cohort

8

Cohort

study

●

A group or groups of individuals to be followed forward and defined

on ●

Status of exposure

to a specified risk factor for a disease (e.g., drug)●

Status of disease

presence●

Exposure is defined at time of cohort entry and is assessed before outcome

●

Drug

registry

: is a cohort of patients defined by exposure to the drug●

Provide information about:●

Incidence data of outcome(s) of interest●

Disease course between exposed and non-exposed patients●

Possible delayed drug effect of newly marketed drug

+ Rx+ Rx

Cohort (prospective)

Outcome?Outcome?

ExposureExposure TimeTime retrospective (if existing data)

9

Cross-sectional

survey

●

Exposure and disease status are assessed simultaneously at a specific time point

among individuals in a well-defined population

●

Provide information about:●

Frequency and characteristics of a disease●

Health status and health care needs●

Prevalence of disease or other health outcomes in certain occupations

●

Conditions of use of a drug

(i.e. at treatment initiation)

Cross-sectional (one snapshot)

Cross-sectional

10

Case-control study

●

Goal is to

compare

cases with a disease

to controls without the disease, looking for differences in antecedent exposures

Cases

Controls

Exposed?

Exposed?

●Provide information about:●Multiple causes (number of exposures) of a single disease●Allow to study rare

diseases

Case-control (retrospective)

11

Advantages

& Disadvantages

of

PE study designs

Design Advantages Disadvantages

Cross-sectional ● Logistically easier & faster● Less expensive

●

Not always possible to distinguish whether the exposure precedes or follows the disease since exposure and disease status are measured at the same point in time● No longitudinal data

Cohort ● Can study multiple outcomes● Can study uncommon exposures● Selection bias less likely● Unbiased exposure data

● Possibly biased outcome data● More expensive●

If done prospectively, may take years to complete

Case-control ● Can study multiple exposures● Can study uncommon diseases● Logistically easier & faster● Less expensive

● Control selection problematic● Possibly biased exposure data

12

Different

databases

available

●

Medical claims or hospital administrative databases●

US: PharMetrics, Premier, LabRx

●

Population-based registries●

Danish and Swedish registry

●

Automated medical records●

UK: THIN, GPRD

●

US: Department of Defense, GE

13

Agenda

●

Background on Pharmacoepidemiology●

Current

European

PV regulations

●

Place of Pharmacoepidemiology

in Pharmacovigilance●

Illustrative cases

●

Conclusion

14

PV & RMP Regulations are linked to crises!

15

Pharmaceutical regulation evolution since 50 years: toward risk management…

2002 2004 2006 2007 20102005 2009

ICH E2E

PDUFA III

CIOMS VI: Management of safety information from Clinical Trials (not regulatory)

• Regulation n°726/2004 -

art 6• Directive 2004/27/EC -

art 8(3)

FDAAA –

PDUFA IV (REMS)

Guidelines on Risk Management Systems

All EU-RMP regulations now in VOL9A, Part I, Section 3

EU -

RMP Template

2008

Guideline on Risk Management ATMPs

2012

New EU Pharmacovigilance legislation

ICH:

International Conference

on Harmonisation; CIOMS: Council for international organizations of Medical Sciences; ATMP: Advanced Therapy

Medicinal

Product; REMS: Risk

Evaluation and Mitigation Strategy; PDUFA: Prescription Drug User Fee Act;FDAAA: Food and Drug Administration Amendments Act

Draft REMS guidance

•Premarketing Risk Assessment•Good PV Practices & PE•Development and Use of

Risk Minimization Action Plans

16

●

Mar 2004: EU directive 2001/83/CE amended by the EU directive 2004/27/CE (EU directive 2001/83/CE amended by the EU directive 2004/27/CE (art 8(3))art 8(3))

•

Introduction of the inclusion of “A detailed description of the pharmacovigilance and, where appropriate, of the risk management system”

within a Market Authorization (MA) application

●

Dec 2004: ICH E2E Pharmacovigilance Planning (CHMP/ICH/5716/3)ICH E2E Pharmacovigilance Planning (CHMP/ICH/5716/3)

•

Intended to aid in planning pharmacovigilance

activities

(e.g., preparation for early post-marketing period of a new drug)

•

Main focus on Safety Specifications and Pharmacovigilance

Plan

that might be submitted at the time of MA application

●

Nov 2005: Guideline on Risk Management Systems (CHMP/96268/2005)Guideline on Risk Management Systems (CHMP/96268/2005)

•

Form of the risk management system, a RMP, should be presented to CAs●

Jan 2007: VolVol

9A 9A ““Rules Governing Medicinal Products in the European UnionRules Governing Medicinal Products in the European Union””•

Legal Basis of the MAH’s

Obligations for

Human Pharmacovigilance

●

Nov 2008: VolVol

9A updated with details on Post9A updated with details on Post--Authorization Safety StudiesAuthorization Safety Studies

(PASS),

defined as:

•

“pharmacoepidemiological

study or clinical trial

carried out in accordance with the terms of a marketing authorization […] This includes all company-sponsored studies conducted within the EU, and those conducted outside the EU as part of a Risk Management Plan,

where the investigation of safety

is among study objectives.”

European regulations

17

European

regulations Situations when an EU-RMP is required

●

EU-RMP should

be

submitted

with the application for a new marketing authorisation

for●

Any

product containing

a new active substance●

A similar

biological

medicinal

product●

A generic/hybrid

medicinal

product where a safety concern

requiring

additional

risk minimisation activities has been identified with the reference medicinal

product●

with an application for a pediatric use marketing authorization●

with an application involving

a significant

change in a marketing authorisation (e.g. new dosage form, new route of administration, new manufacturing

process of a biotechnologically-derived

product, significant

change in indication including pediatric indication) unless

it has been agreed

with the Competent

Authority

that submission is not required

●

On request from a Competent

Authority

(both pre-and post-

authorisation)●

On the initiative of a MAA/MAH when they identify

a safety concern

with a medicinal

product at any stage of its life cycle

Refs: Guideline on Risk Management Systems

(CHMP/96268/2005)

incorporated in Vol

9A, Part I, Section 3

in Mar 2007; Updated

Vol9A

in Sep 2008

18

●

Dec 2010: New EU PV legislationNew EU PV legislation

in force in July 2012 ●

“Conditional”

Marketing Authorisation granted with conditions and deadlines

Penalties in case of non-compliance (Suspension or revocation of MA or Financial penalties)

●

Revised & broader definition of PASS

“Any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures”

●

MAH can be required to conduct also

Post-Authorisation Efficacy (PAES) studies*:

To collect data in everyday medical practice (observational)

Request at any time in the product life cycle from initial MA

European regulations New!

* Ref

: Amendment

EU Directive 2010/84/E-

31 Dec 2010

19

New EU PV legislation

in force in July 2012 PhV

Risk Assessment Committee

(PRAC)

●

PRAC

= New scientific committee at the EMA= New scientific committee at the EMA

with a key role in the pharmacovigilance assessments

●

Scope: All

medicinal products (RMP, PSUR, PASS, signal detection, Urgent Union Procedure)●

Replaces the CHMP Pharmacovigilance Working Party (PhWP)●

At the same level

as the CHMP●

Composition:

Representatives from MS with competence in PhV

and risk assessment

6 independent scientific experts appointed by the EU Commission

Representatives from Healthcare Professionals (1+1) and Patient associations (1+1)●

Decision making

●

Final responsibility for opinion on the risk-benefit remains with CHMP (centralised

products)

or CMDh

(other products);●

CHMP or CMDh

should rely on the recommendations of the PRAC

CHMP: Committe

for human

medicinal

products; CMDh: Committe

for

mature products

New!

20

New EU PV legislation Impact on Post-Marketing activities (PSURs, RMPs, PASS,

PAES…)●●

Systematic development of postSystematic development of post--authorization non interventional (realauthorization non interventional (real--life) life) studiesstudies●

For safety (risk) as well as efficacy (benefit) => effectiveness●

Pharmacoepidemiology methods (databases, cohorts, registries…)●

Link with the ENCePP

program from the EMA●

New regulatory process for endorsement

●●

Repetitive Benefit EvaluationRepetitive Benefit Evaluation●

Medical “efficacy”

expertise to be maintained and resourced during the whole life-cycle

●●

Development of methods for assessing effectiveness of minimizatiDevelopment of methods for assessing effectiveness of minimizationon●

Accurate and detailed ongoing evaluation of exposure●

Develop methods for drug utilization studies

●●

ProactivityProactivity

in signal detection and labeling updatesin signal detection and labeling updates

21

Agenda

●


Current

European

PV regulations

●



Illustrative cases

●

Conclusion

22

Safety obtained during Clinical Development is only the tip of the iceberg…

At the time of clinical development

Post-marketing surveillance

BenefitsBenefitsIntrinsic ToxicityIntrinsic Toxicity

Medication errorsMedication errorsPoor compliancePoor compliance

Wrong populationWrong populationRisk perceptionRisk perception

Efficacy+

Usage

+Condition of use

RisksRisks

Product defectsProduct defects

Tolerance

BenefitsBenefitsIntrinsic ToxicityIntrinsic Toxicity

Medication errorsMedication errorsPoor compliancePoor compliance

Wrong populationWrong populationRisk perceptionRisk perception

Efficacy+

Usage

+Condition of use

RisksRisks

Product defectsProduct defects

Tolerance

BenefitsBenefits

RisksIntrinsic Toxicity


Efficacy

ToleranceBenefitsBenefits



Efficacy

Tolerance

23

Limited safety data at time of drug approval

●

Limited number of people exposed in RCTs●

Some type of patients may have never been enrolled

●

Lack of detection of uncommon/rare or delayed adverse drug reactions (ADRs)

●

ADRs

specific to high risk populations due to misuse of the drugs by prescribers or patients

●

Causal inference may be difficult to draw

PharmacoepidemiologyPharmacoepidemiology

cancan

contributecontribute

information about information about drugdrug

safetysafety

and and effectivenesseffectiveness

in real life setting in real life setting thatthat

isis

not not availableavailable

fromfrom

premarketingpremarketing

studiesstudies

24

Post approval Safety data

Pharmacovigilance Plan

[Risk assessment]

Continuous characterization of safety profile &

detection of newly emerging safety signals or risks

Routine Routine pharmacovigilancepharmacovigilance•Collection of ADRs•Specific forms for documentation•Expedited Reporting•Signal detection•Analysis•PSURs•DSURs

(if applicable)

Additional PV activitiesAdditional PV activities•Active surveillance (Sentinel sites (eg, OMOP), intensive monitoring schemes or )•PE studies (Case control, Cohort…)•Clinical trials•Nonclinical studies

25

Post approval Risk Minimization Activities

Prevent or minimize

safety risks

Evaluation of the need for risk minimization

Routine risk minimization:Routine risk minimization:• Legal status • Pack size• Package leaflet (PIL)• Labeling (SPC, USPI,…)

Additional Risk Minimization activities:Additional Risk Minimization activities:• Communication plan• Reminder tools• Restricted prescription • Drug registry

26

Risk Management is an iterative process! Risk assessment, Risk minimization & its effectiveness

:Sa

fety

Ris

kA

sses

smen

t

Routine: labeling

Routine: pharmacovigilance activities including PS(U)Rs

Additional: PV plan to identify and characterize specific risks, e.g.:• PASSPASS

(i.e., pharmacoepidemiology or non-clinical investigations)• Clinical studies• Others

Drug utilization studiesDrug utilization studies

(e.g., using existing databases or prescription survey)

Additional:Communication and education (e.g., Continuous Medical Education)Reminder tools (e.g. physician brochure or patient card)Restricted prescription (e.g., specialists only prescribers) Drug registry

EffectivenessA

ssessment

Min

imiz

atio

n A

ctiv

ities

27

Final outcomesindicators

Process indicators

Effectiveness of minimization measures

1.

Implementation of measures-

Measures by increasing level of constraints

-

Communication plan-

Reminder tools (i.e. prescriber checklist)-

Restricted prescription-

Mandatory drug registry-

1st assessment:

success of implementation

2.

Assessment of effectivenesswhat is the IMPACT?

Clinical knowledge

Score

Clinical actions

Appropriate use

ADR occurrence or severity

Frequency of events

28

In Summary: Main

features of post-marketing studies

●●

ObjectivesObjectives●

Safety (risk assessment and characterization)•

Causal relationship for a potential risk•

Quantification (incidence)•

Preventability: risk factors, early detection, markers & surrogates●

Other objectives•

Efficacy (benefit)•

Use (drug utilization studies) •

Cost/effectiveness

●●

““RealReal--lifelife””●

Real conditions of use: per labeling, distribution system, and reimbursement determined by the local health care organization

●

Observational setting, opposed to controlled/randomized clinical

trial situations●

Risk assessment in conditions of minimization

●●

Methods = (pharmaco)Methods = (pharmaco)--epidemiologyepidemiology●

Epidemiology designs and methods to be developed

29

Some

other

practical

aspects/questions

●●

WhenWhen

do do wewe

have to have to startstart

studiesstudies? For how long?? For how long?●

Quickly

after

launch●

Usually

several

years, until

there

is

enough

evidence

on drug

use

●●

WhereWhere

do do wewe

have to have to implementimplement

studiesstudies??●

A diversified

set of countries (i.e. at

least two

European

countries), and where

requested

or needed

as per local country

●●

WhatWhat

isis

the the reasonablereasonable

goal to goal to reachreach??●

Practical

goals to be

set, based

on labeling, past

experience, and literature

(perfect

use probaly

never

observed)

●

Goals to be

agreed

with

regulators

before

starting

the study

●●

WhatWhat

do do wewe

do do withwith

studystudy

resultsresults??●

Submission

to regulatory

agencies

(i.e.

at

time of RMP updates and/or PSUR updates)●

Results

to be

interpreted

cautiously, considering

limitations of data sources & bias

30

Agenda

●


Current

European

PV regulations

●



Illustrative cases

●

Conclusion

31

Example of specific PV plan to investigate risk of hepatic risk of hepatic injuryinjury

and Risk Minimization Plan to minimize this risk

Specific

PV plan

Elevation of transaminases

enzymes (hepatotoxicity

?)

Standard PV:

ADRs Enhanced PV: use of specific form for fast capture and best evaluation of severe/serious hepatic cases

Pharmaco-epi

studies:In databases (Pharmo

in NL, Saskatchewan in Canada, GPRD in the UK, HMOs in the US) to assess risk of liver injury

Clinical studies: to increase patient exposure enhancing profile understanding /Real-life pragmatic CTMechanistic studies

(in-vitro, pharmaco-genetic, Proteonomics/ metabonomics

study)

Hepatic surveillance programme

(HSP): Voluntary although target all patients on Drug X to assess risk of liver injury

Specific

Minimization

plan

Labeling: monthly monitoring of liver enzymes (stopping rules)ContraindicationLegal status (prescription by specialists only)Limitation of prescription size (30 days)

Educational program:Introductory letter to prescribers, prescriber’s guide, patient information brochure, prescriber’s pocket card, patient card

Reminder

tools: prescriber

check list

for LFT monitoringControlled

dispensing: patients with

specific

genotyping

not authorized

to receive

drug

(if applicable)

Effectiveness

of tools

(PE studies)Cross-sectionnal

surveys

(market

research)Drug utilization

study

using

databasesDrug utilization

data through

HSP

32

Example of Nested Case Control Study Using US claims databases to evaluate severe liver injury

associated with drug x

Cases (N = 414) Controls

(N = 40,572)

Age (mean±SD), years 65.1 (11.3) 65.6 (10.8)

Sex

(women) 134 (32.4%) 12,887 (31.8%)

CHF 187 (45.2%) 11,143 (27.5%)

Diabetes 139 (33.6%) 9,620 (23.7%)

Hypertension 314 (75.8%) 29,187 (71.9%)

Stroke 43 (10.4%) 3,210 (7.9%)

AMI 37 (8.9%) 2,833 (7.0%)

Tx

duration

of drug

x(median, min, max), days

44 (0, 2274) 0 (0, 3272)

Tx

duration, others

in class 0 (0, 2475) 90 (0, 3826)

Cases Controls Crude

ORAdjusted

OR(95%CI)

Drug X vs. not

184 /230

11,782 /28,790

1.8 1.7 [1.3, 2.2]

Patients treated with drug X have 1.7 Patients treated with drug X have 1.7 times higher risk of severe liver injury times higher risk of severe liver injury than those not treated with drug Xthan those not treated with drug X

33

Example of retrospective cohort using databases to evaluate severe hepatic injury

associated with telithromycin

●Data sources: ●

Ingenix Proprietary Research Database

●

PHARMetrics Integrated Outcome Database

●Design: retrospective cohort●Applications:

●

The studies were part of the telithromycin

Risk Management Plan

commitment●

The results were presented to the FDA Advisory Committee in December 2006

34

Crude and Adjusted Risk Ratios of Severe Hepatic Injury

Crude Adjusted*

Risk ratio 95% C.I. Risk ratio 95% C.I.

AUG ** 1.00 N/A 1.00 N/A

CLA 2.00 0.82 –

4.85 1.95 0.80 –

4.73

MOX 2.90 1.17 –

7.19 2.58 1.04 –

6.43

TEL 1.37 0.51 –

3.71 1.44 0.53 –

3.89

*

Covariates age, sex, prior history of liver disease, and Charlson Index were adjusted in the GEE model

**

Augmentin (AUG) was used as a reference group in the GEE modelCLA=clarithromycin; MOX= moxifloxacin; TEL= telithromycin

35

96,7 98,9 99,798,5

49,143,1

64,2

49,1

0

10

20

30

40

50

60

70

80

90

100

Switzerland (N=273) Germany (N=369)

%

No use in CHF classIV/unstable III

No concomitant use ofCYP3A4 inhibitors

Creatinine plannedwithin one week

Creatinine plannedwithin one month

Example of evaluation of drug utilization using cross- sectional survey

Cross-sectional

surveys

to measure

prescribers’

understanding

of labeling

recommendations

and subsequent

compliance

to

contraindications

and laboratory

monitoring of Drug X

36

Example of evaluation of drug utilization

using

US claims database

Patient profile at

initiation of Drug X

Contraindication

N % [95%CI]

Diagnosis of AF/AFL 1,712 94.1 [92.9, 95.1]

Diagnosis of hypertension 1,352 74.3 [72.2, 79.6]

Diagnosis of diabetes 361 19.8 [18.0, 21.7]

Diagnosis of stroke 118 6.5 [5.4, 7.7]

Diagnosis of AMI 85 4.7 [3.7, 5.7]

≥ 1 risk factors* 1,454 79.9 [78.0, 81.7] *including hypertension, diabetes, stroke, AMI, or aged > 70 years

Prevalence of AF/AFL and cardiovascular risk factors (N = 1,820)

Worsening /hospitalized CHF # of cases % [95%CI]

Within 0-30 days prior to drug x prescription 70 3.8 [3.0, 4.8]

Prevalence of worsening / hospitalized CHF within 0-30 days before drug x prescription (N =1,820)

37

Agenda

●


Current

European

PV regulations

●



Illustrative cases

●

Conclusion

38

●

Post-marketing evaluation methods are needed in the domain of Pharmacovigilance:●

To increase knowledge on drug safetyknowledge on drug safety

in real life setting ●

To increase knowledge on drug utilizationknowledge on drug utilization

in real life setting ●

To address new PV regulations and increasing requirements address new PV regulations and increasing requirements regarding PV assessment using pharmacoepidemiology

methods

A specific competency in A specific competency in PharmacoEpidemiologyPharmacoEpidemiology

is required is required

The European Network of Centres

for Pharmacoepidemiology and Pharmacovigilance

(ENCePP)•

Project led by the

European Medicines Agency (EMA)•

Goal: strengthen the post-authorisation

monitoring of medicinal products in Europe by facilitating the conduct of multi-centre, independent, post-authorisation

studies focusing on safety and on benefit/risk

http://www.encepp.eu/

Conclusion

39

Thank you!Thank you!

ありがとうありがとう !!謝謝謝謝 !!

DankeDanke!!GraciasGracias!!

MerciMerci!!

Châtenay-Malabry January 2013 40

Back-ups

41

Advantages

& Disadvantages

of

data sources

Data sources Advantages Disadvantages

Field studies ●

All data specific

to the study

needs

may

be

collected

and recorded in a consistent way for each patients (usually based on a study protocol) ● General population based●Timely information available for patients

●Regulatory

requirements

of general

AE collection, not specific

to the study●Participation rates may

be

low, questionable

representativeness●

Limited number

of study

subjects

may

be

pratically

planned

for a study●Selection

bias: (study

subjects

enrolled

may

be

different

from

the target

population)●voluntary

patients patient most

frequently

seen

in consultation «

well-

treated

»

patients●More expensive

and time-

consuming

42

Advantages

& Disadvantages

of

data sources

Data sources Advantages Disadvantages

Database

studies ●

Data already

collected, avoid

recall

bias●

Usually

large population based

data ●

All patients in the database

are included

(limited

selection

bias)●

More cost-efficient and less

time-consuming

● Lag

time of data availability●Data limited

to what’s

available

in the database●Difficult

to get

a sufficient

number

of study

subjects, if the exposure

of interest

is

uncommon●Data specific

to the database

population, may

not be

generalizable

43

ICH and CIOMS

●

ICH E2E -

Pharmacovigilance Planning (PVP)●

Tripartite harmonized guideline finalized (step 4) in November 2004●

Intended to aid in planning pharmacovigilance activities (eg, preparation for early post-marketing period of a new drug)

●

Main focus on Safety Specifications and Pharmacovigilance Plan that might be submitted at the time of license application

●

CIOMS VI -

Management of Safety Information from Clinical Trials (2005)●

Basis of Risk Management during development

ICH: International Conference

on Harmonisation; CIOMS: Council for international organizations of Medical Sciences

44

New EU PV legislation Extract from the original text

New Article 22a•

After

the granting

of a marketing authorisation, the national competent

authority

may

impose an obligation on the marketing authorisation

holder: •

(a) to conduct

a post-authorisation

safety

study

if there

are concerns

about the risks

of an authorised

medicinal

product. If the same

concerns

apply

to more than

one medicinal

product, the national competent

authority

shall, following

consultation with

the Pharmacovigilance Risk

Assessment

Committee, encourage the marketing authorisation

holders

concerned

to conduct

a joint post-authorisation

safety

study; •

(b) to conduct

a post-authorisation

efficacy

study

when

the understanding

of the disease

or the clinical

methodology

indicate

that

previous

efficacy

evaluations

might

have to be

revised

significantly. The obligation to conduct

the post-

authorisation

efficacy

study

shall

be

based

on the delegated

acts

adopted

pursuant

to Article 22b while

taking

into

account

the scientific

guidance referred

to in Article 108a.

•

The imposition of such

an obligation shall

be

duly

justified, notified

in writing, and shall

include

the objectives and timeframe

for submission

and conduct

of the study.

»

* Ref

: Amendment

EU Directive 2010/84/E-

31 Dec 2010

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