December 2011
CMDh/204/2005
Decentralised Procedure
RMS Day 70 Preliminary Assessment Report
CLINICAL
<Invented Name>
<(Active Substance)>
AB/H/{nnnn} /{nnn}/DC
Applicant:
Reference Member State:
Start of the procedure:
Date of this report:
Deadline for comments:
<Invented name>, <Procedure number>
1/18
Day 70-PrAR-C
TABLE OF CONTENTS
I.
I.1
I.2
II.
II.1
II.1.1
II.1.2
II.1.3
II.1.4
II.1.5
II.1.6
II.1.7
II.1.8
II.1.9
II.1.10
II.1.11
II.1.12
II.2
II.2.1
II.2.2
II.2.3
II.2.4
II.2.5
II.2.6
II.2.7
II.2.8
III.
III.1
III.2
III.2.1
III.2.2
III.3
III.4
III.5
III.6
IV.
IV.1
IV.2
IV.3
IV.4
IV.5
IV.6
IV.7
IV.8
IV.9
IV.10
IV.11
IV.12
V.
V.1
V.2
INTRODUCTION .......................................................................................................................... 5
Type of Application and aspects on development ....................................................................... 5
GCP aspects .................................................................................................................................... 5
CLINICAL PHARMACOLOGY ................................................................................................. 5
Pharmacokinetics ........................................................................................................................... 5
Introduction ........................................................................................................................... 5
Methods .................................................................................................................................. 5
Absorption .............................................................................................................................. 6
Distribution ............................................................................................................................ 6
Elimination ............................................................................................................................. 6
Dose proportionality and time dependency ......................................................................... 6
Intra- and inter-individual variability ................................................................................. 7
Pharmacokinetics in target population ................................................................................ 7
Special populations ................................................................................................................ 7
Interactions ............................................................................................................................ 8
Exposure relevant for safety evaluation .............................................................................. 8
Assessor’s overall conclusions on pharmacokinetics .......................................................... 8
Pharmacodynamics ........................................................................................................................ 8
Introduction ........................................................................................................................... 8
Mechanism of action.............................................................................................................. 8
Primary pharmacology ......................................................................................................... 8
Secondary pharmacology ...................................................................................................... 8
Relationship between plasma concentration and effect ..................................................... 8
Pharmacodynamic interactions with other medicinal products or substances ................ 9
Genetic differences in PD response ...................................................................................... 9
Assessor’s overall conclusions on pharmacodynamics ....................................................... 9
CLINICAL EFFICACY .............................................................................................................. 10
Introduction .................................................................................................................................. 10
Dose-response studies and main clinical studies ........................................................................ 10
Dose response study(ies) ...................................................................................................... 10
Main study(ies)..................................................................................................................... 10
Clinical studies in special populations ......................................................................................... 13
Analysis performed across trials (pooled analyses AND meta-analysis).................................... 14
Supportive study(ies).................................................................................................................... 14
Assessor’s overall conclusions on clinical efficacy ..................................................................... 14
CLINICAL SAFETY ................................................................................................................... 14
Introduction .................................................................................................................................. 14
Patient exposure ........................................................................................................................... 14
Adverse events .............................................................................................................................. 14
Serious adverse events and deaths .............................................................................................. 14
Laboratory findings ..................................................................................................................... 15
Safety in special populations ....................................................................................................... 15
Immunological events .................................................................................................................. 15
Safety related to drug-drug interactions and other interactions ............................................. 15
Discontinuation due to AES......................................................................................................... 15
Post marketing experience/Risk management .................................................................. 15
Proposals for post authorisation follow up (post marketing surveillance) .................... 15
Assessor’s overall conclusions on clinical safety ............................................................... 15
PHARMACOVIGILANCE ........................................................................................................ 16
Pharmacovigilance system .......................................................................................................... 16
Risk management plan ................................................................................................................ 16
<Invented name>, <Procedure number>
2/18
Day 70-PrAR-C
VI.
LIST OF QUESTIONS AS PROPOSED BY THE RMS ......................................................... 18
VII.
RECOMMENDED CONDITIONS FOR MARKETING AUTHORISATION AND
PRODUCT INFORMATION .................................................................................................................. 18
<Invented name>, <Procedure number>
3/18
Day 70-PrAR-C
LIST OF ABBREVIATIONS
<Invented name>, <Procedure number>
4/18
Day 70-PrAR-C
CLINICAL CRITICAL ASSESSMENT
I.
INTRODUCTION
I.1
Type of Application and aspects on development
I.2
GCP aspects
II.
CLINICAL PHARMACOLOGY
II.1
Pharmacokinetics
II.1.1
Introduction
II.1.2
Methods

Analytical methods
Assessor’s comment

Pharmacokinetic data analysis
Assessor’s comment

Statistical analysis
Assessor’s comment
<Invented name>, <Procedure number>
5/18
Day 70-PrAR-C
II.1.3
Absorption

Bioavailability
Assessor’s comment

Bioequivalence
Assessor’s comment

Influence of food
Assessor’s comment
II.1.4
Distribution
Assessor’s comment
II.1.5
Elimination

Excretion
Assessor’s comment

Metabolism
Assessor’s comment

Inter-conversion
Assessor’s comment

Pharmacokinetics of metabolites
Assessor’s comment

Consequences of possible genetic polymorphism
Assessor’s comment
II.1.6
Dose proportionality and time dependency

Dose proportionality
Assessor’s comment

Time dependency
Assessor’s comment
<Invented name>, <Procedure number>
6/18
Day 70-PrAR-C
II.1.7
Intra- and inter-individual variability
Assessor’s comment
II.1.8
Pharmacokinetics in target population
Assessor’s comment
II.1.9
Special populations

Impaired renal function
Assessor’s comment

Impaired hepatic function
Assessor’s comment

Gender
Assessor’s comment

Race
Assessor’s comment

Weight
Assessor’s comment

Elderly
The studied population should be described
OR
Age 65-74
Older subjects
number /total number
PK Trials
Age 75-84
Age 85+
Controlled Trials
Non Controlled trials
Assessor’s comment

Children
Assessor’s comment
<Invented name>, <Procedure number>
7/18
Day 70-PrAR-C
Assessor's overall comments on pharmacokinetics in special populations
II.1.10
Interactions

In vitro
Assessor’s comment

In vivo
Assessor’s comment
Assessor's overall comments on Interactions
II.1.11
Exposure relevant for safety evaluation
Assessor’s comment
II.1.12
Assessor’s overall conclusions on pharmacokinetics
II.2
Pharmacodynamics
II.2.1
Introduction
II.2.2
Mechanism of action
Assessor’s comment
II.2.3
Primary pharmacology
Assessor’s comment
II.2.4
Secondary pharmacology
Assessor’s comment
II.2.5
Relationship between plasma concentration and effect
Assessor’s comment
<Invented name>, <Procedure number>
8/18
Day 70-PrAR-C
II.2.6
Pharmacodynamic interactions with other medicinal products or substances
Assessor’s comment
II.2.7
Genetic differences in PD response
Assessor’s comment
II.2.8
Assessor’s overall conclusions on pharmacodynamics
<Invented name>, <Procedure number>
9/18
Day 70-PrAR-C
III.
CLINICAL EFFICACY
III.1
Introduction
Example table for study details:
Study ID
III.2
No. of
study
centres /
locations
Design
Study
Posology
Study
Objective
Subjs by
arm
entred/
compl.
Duration
Gender
M/F
Median
Age
Diagnosis
Incl.
criteria
Primary
Endpoint
Dose-response studies and main clinical studies
Assessor’s comment
III.2.1
Dose response study(ies)
Assessor’s comment
III.2.2
Main study(ies)
Assessor’s comment
Methods

Study Participants
Assessor’s comment

Treatments
Assessor’s comment

Objectives
Assessor’s comment

Outcomes/endpoints
Assessor’s comment

Sample size
Assessor’s comment

Randomisation
Assessor’s comment
<Invented name>, <Procedure number>
10/18
Day 70-PrAR-C

Blinding (masking)
Assessor’s comment

Statistical methods
Results

Participant flow
(Use and amend as appropriate)
Excluded (n=…)
Not meeting Inclusion criteria
Refused to participate (n=…)
Other reasons (n=…)
Randomised (n=…)
Allocated to intervention (n=…)
Received allocated intervention (n=..)
Did not receive Allocated intervention;
give reasons (n=..)
Follow-up
Allocated to intervention (n=…)
Received allocated intervention (n=..)
Did not receive Allocated intervention;
give reasons (n=..)
Lost to follow-up; give reasons
(n=..)
Discontinued intervention; give
reasons (n=..)
Lost to follow-up; give reasons
(n=..)
Discontinued intervention; give
reasons (n=..)
Analysis
Allocation
Enrolment
Assessed for
Eligibility (n=…)
Analysed (n..)
Excluded from analysis; give
reasons (n=..)
Analysed (n..)
Excluded from analysis; give
reasons (n=..)
Assessor’s comment

Recruitment
Assessor’s comment

Conduct of the study
Assessor’s comment

Baseline data
Assessor’s comment
<Invented name>, <Procedure number>
11/18
Day 70-PrAR-C

Numbers analysed
Assessor’s comment

Outcomes and estimation
Assessor’s comment

Ancillary analyses
Assessor’s comment
•
Summary of main efficacy results
Results should be described.
OR
<The following tables summarise the efficacy results from the main studies supporting the present
application. These summaries should be read in conjunction with the discussion on clinical efficacy as
well as the benefit risk assessment (see later sections).>
Table XXX. Summary of efficacy for trial <trial>
Title: <title>
Study identifier
<code>
Design
<free text>
Duration of main phase:
Duration of Run-in phase:
Duration of Extension phase:
Hypothesis
Treatments groups
<Superiority> < Equivalence> <Non-inferiority> <Exploratory: specify>
<group descriptor>
<Co>Primary
endpoint
<label>
<treatment>. <duration>, <number
randomized>
<treatment>. <duration>, <number
randomized>
<treatment>. <duration>, <number
randomized>
<free text>
<Secondary>
<other:
specify>
endpoint
<Secondary>
<other:
specify>
endpoint
<label>
<free text>
<label>
<free text>
<group descriptor>
<group descriptor>
Endpoints and
definitions
Database lock
<time>
<time> <not applicable>
<time> <not applicable>
<date>
<Invented name>, <Procedure number>
12/18
Day 70-PrAR-C
Results and Analysis
Analysis description
Analysis population
and time point
description
Descriptive statistics
and estimate
variability
Primary Analysis
<Intent to treat> <Per protocol> <other: specify>
<time point>
Treatment group
Number of
subject
<endpoint>
(<statistic>)
<variability
statistic>
<endpoint>
(<statistic>)
<variability
statistic>
<endpoint>
(<statistic>)
<variability
statistic>
Effect estimate per
comparison
<Co->Primary
endpoint
<group
descriptor>
<group
descriptor>
<group
descriptor>
<n>
<n>
<n>
<point
estimate>
<point
estimate>
<point
estimate>
<variability>
<variability>
<variability>
<point
estimate>
<point
estimate>
<point
estimate>
<variability>
<variability>
<variability>
<point
estimate>
<point
estimate>
<point
estimate>
<variability>
<variability>
<variability>
Comparison groups
<group descriptors>
<test statistic>
<point estimate>
<variability statistic>
<variability>
P-value
<P-value>
<<Co->Primary >
<Secondary><ot
her: specify>
endpoint
Comparison groups
<group descriptors>
<test statistic>
<variability statistic>
P-value
<point estimate>
<variability>
<P-value>
<<Co->Primary >
<Secondary><ot
her: specify>
endpoint
Comparison groups
<group descriptors>
<test statistic>
<variability statistic>
P-value
<point estimate>
<variability>
<P-value>
Notes
<free text>
Analysis description
<Secondary analysis> <Co-primary Analysis> <Other, specify: >
III.3
Clinical studies in special populations
Assessor’s comment
<Invented name>, <Procedure number>
13/18
Day 70-PrAR-C
III.4
Analysis performed across trials (pooled analyses AND meta-analysis)
Assessor’s comment
III.5
Supportive study(ies)
Assessor’s comment
III.6
Assessor’s overall conclusions on clinical efficacy
IV.
CLINICAL SAFETY
IV.1
Introduction
Assessor’s comment
IV.2
Patient exposure
Example of a table: Patient exposure (cut off)
Patients enrolled
Patients exposed
Patients exposed
to the proposed
dose range
Patients with
long term* safety
data
Placebo-controlled
Active -controlled
Open studies
Post marketing
Compassionate use
* In general this refers to 6 months and 12 months continuous exposure data, or intermittent exposure.
Assessor’s comment
IV.3
Adverse events
Assessor’s comment
IV.4
Serious adverse events and deaths
Assessor’s comment
<Invented name>, <Procedure number>
14/18
Day 70-PrAR-C
IV.5
Laboratory findings
Assessor’s comment
IV.6
Safety in special populations
AE Table
Age <65 yrs
65-74 yrs
75-84 yrs
85 +
Total
Fatal
Serious
Withdrawal
CNS (confusion/extrapyramidal)
AE related to falling
CV events
Cerebrovascular events
Infections
Assessor’s comment
IV.7
Immunological events
Assessor’s comment
IV.8
Safety related to drug-drug interactions and other interactions
Assessor’s comment
IV.9
Discontinuation due to AES
Assessor’s comment
IV.10
Post marketing experience/Risk management
Assessor’s comment
IV.11
Proposals for post authorisation follow up (post marketing surveillance)
Assessor’s comment
IV.12
Assessor’s overall conclusions on clinical safety
<Invented name>, <Procedure number>
15/18
Day 70-PrAR-C
V.
PHARMACOVIGILANCE
V.1
Pharmacovigilance system
<The applicant has provided documents that set out a detailed description of the system of
pharmacovigilance. A statement signed by the applicant and the qualified person for pharmacovigilance,
indicating that the applicant has the services of a qualified person responsible for pharmacovigilance and
the necessary means for the notification of any adverse reaction occurring either in the Community or in a
third country has been provided. >
<The RMS considers that the Pharmacovigilance system, version <X> as described by the applicant fulfils
the requirements and provides adequate evidence that the applicant has the services of a qualified person
responsible for pharmacovigilance and has the necessary means for the notification of any adverse
reaction suspected of occurring either in the Community or in a third country.>
<The RMS considers that the Pharmacovigilance system, version <X> as described by the applicant has
the following deficiencies:<list the deficiencies>
<Provided that the deficiencies are rectified prior to the applicant placing the medicinal product on the
market, the RMS may consider that the Pharmacovigilance system will fulfil the requirements. The
applicant must ensure that the system of pharmacovigilance is in place and functioning before the product
is placed on the market>
Assessor’s comment
V.2
Risk management plan

Safety Specification

Pharmacovigilance plan

Evaluation of the need for risk minimisation measures

Risk minimisation plan
Assessor’s comment
<Invented name>, <Procedure number>
16/18
Day 70-PrAR-C
LIST OF REFERENCES
<Invented name>, <Procedure number>
17/18
Day 70-PrAR-C
VI.
LIST OF QUESTIONS AS PROPOSED BY THE RMS
Clinical aspects
Potential Serious Risks to Public Health
Pharmacokinetics
Pharmacodynamics
Efficacy
Safety
Pharmacovigilance
Points for clarification
Pharmacokinetics
Pharmacodynamics
Efficacy
Safety
Pharmacovigilance
VII.
RECOMMENDED CONDITIONS FOR MARKETING
AUTHORISATION AND PRODUCT INFORMATION
<Invented name>, <Procedure number>
18/18
Day 70-PrAR-C