<Co->Rapporteur clinical critical assessment report
Clinical aspects – Extension of Indication
<Invented name>
<(Active substance)>
EMEA/H/C/<xxx>
<MAH>
<Worksharing applicant> (WSA)
Rapporteur:
Co-rapporteur:
EMA PTL:
Start of the procedure:
Date of this report:
Deadline for comments:
Table of contents
1. Introduction ............................................................................................ 6
1.1. Type of application and aspects on development ...................................................... 6
1.2. GCP aspects ........................................................................................................ 6
1.3. Orphan medicinal products .................................................................................... 6
2. Clinical pharmacology ............................................................................. 6
2.1. Pharmacokinetics ................................................................................................. 6
2.1.1. Introduction ...................................................................................................... 6
2.1.2. Methods ........................................................................................................... 6
2.1.3. Absorption ........................................................................................................ 6
2.1.4. Distribution ....................................................................................................... 7
2.1.5. Elimination ....................................................................................................... 7
2.1.6. Dose proportionality and time dependency ........................................................... 7
2.1.7. Intra- and inter-individual variability .................................................................... 7
2.1.8. Pharmacokinetics in target population .................................................................. 7
2.1.9. Special populations ............................................................................................ 7
2.1.10. Interactions .................................................................................................... 8
2.1.11. Exposure relevant for safety evaluation .............................................................. 9
2.1.12. Assessor’s overall conclusions on pharmacokinetics .............................................. 9
2.2. Pharmacodynamics ............................................................................................... 9
2.2.1. Introduction ...................................................................................................... 9
2.2.2. Mechanism of action .......................................................................................... 9
2.2.3. Primary pharmacology ....................................................................................... 9
2.2.4. Secondary pharmacology .................................................................................... 9
2.2.5. Relationship between plasma concentration and effect ........................................... 9
2.2.6. Pharmacodynamic interactions with other medicinal products or substances ............. 9
2.2.7. Genetic differences in PD response ...................................................................... 9
2.2.8. Assessor’s overall conclusion on pharmacodynamics .............................................. 9
3. Clinical efficacy........................................................................................ 9
3.1. Introduction......................................................................................................... 9
3.2. Dose-response studies and main clinical studies ..................................................... 10
3.3. Dose response study(ies) .................................................................................... 10
3.4. Main study(ies) .................................................................................................. 10
3.5. Clinical studies in special populations .................................................................... 13
3.6. Analysis performed across trials (pooled analyses AND meta-analysis) ...................... 13
3.7. Supportive study(ies) ......................................................................................... 13
3.8. Assessor’s overall conclusions on clinical efficacy .................................................... 13
4. Clinical safety ........................................................................................ 14
4.1. Introduction....................................................................................................... 14
4.2. Patient exposure ................................................................................................ 14
4.3. Adverse events .................................................................................................. 14
4.4. Serious adverse events and deaths ....................................................................... 14
4.5. Laboratory findings ............................................................................................. 14
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4.6. Safety in special populations ................................................................................ 15
4.7. Immunological events ......................................................................................... 15
4.8. Safety related to drug-drug interactions and other interactions ................................ 15
4.9. Discontinuation due to AES .................................................................................. 15
4.10. Post marketing experience ................................................................................. 15
4.11. Assessor’s overall conclusions on clinical safety .................................................... 15
5. Pharmacovigilance ................................................................................ 15
5.1. Pharmacovigilance system ................................................................................... 15
5.2. Risk management plan ........................................................................................ 16
6. List of references ................................................................................... 17
7. List of questions as proposed by the <Co->rapporteur ......................... 18
8. Recommended conditions for marketing authorisation and product
information ............................................................................................... 19
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Rev03.13
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Administrative information
Invented name of the medicinal product:
INN (or common name) of the active
substance(s):
Applicant:
Applied Indication(s):
Pharmaco-therapeutic group
(ATC Code):
Pharmaceutical form(s) and strength(s):
Rapporteur contact person:
Name:
Tel:
Fax:
Email:
Co-Rapporteur contact person:
Name:
Tel:
Fax:
Email:
EMA Product Team Leader:
Name:
Tel:
Fax:
Email:
Quality:
Name(s)
Tel:
Fax:
Email:
Names of the Rapporteur assessors
(internal and external):
Non-clinical:
Name(s)
Tel:
Fax:
Email:
Names of the Co-Rapporteur assessors
(internal and external):
Clinical :
Name(s)
Tel:
Fax:
Email:
Quality:
Name(s)
Tel:
Fax:
Email:
Non-clinical:
Name(s)
Tel:
Fax:
Email:
Clinical:
Name(s)
Tel:
Fax:
Email:
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Rev03.13
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List of abbreviations
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Clinical critical assessment
1. Introduction
1.1. Type of application and aspects on development
•
Legal basis
•
Conditional approval/Approval under exceptional circumstances
•
Accelerated procedure
•
Biosimilar application
•
CHMP guidelines/Scientific Advice
•
1 year data exclusivity
•
Significance of paediatric studies
1.2. GCP aspects
1.3. Orphan medicinal products
<According to the conclusion of the COMP (Opinion dated 00/00/00) the prevalence of the “condition”
<state the condition> is <> per 10000 individuals in the EU.>
<N/A>
2. Clinical pharmacology
2.1. Pharmacokinetics
2.1.1. Introduction
2.1.2. Methods
•
Analytical methods
Assessor’s comment
•
Pharmacokinetic data analysis
Assessor’s comment
•
Statistical analysis
Assessor’s comment
2.1.3. Absorption
•
Bioavailability
Assessor’s comment
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•
Bioequivalence
Assessor’s comment
•
Influence of food
Assessor’s comment
2.1.4. Distribution
Assessor’s comment
2.1.5. 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
2.1.6. Dose proportionality and time dependency
•
Dose proportionality
Assessor’s comment
•
Time dependency
Assessor’s comment
2.1.7. Intra- and inter-individual variability
Assessor’s comment
2.1.8. Pharmacokinetics in target population
Assessor’s comment
2.1.9. Special populations
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Rev03.13
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•
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
Age 65-74
PK Trials
Age 75-84
Age 85+
Older subjects
number /total
number
Controlled Trials
Non Controlled trials
Assessor’s comment
•
Children
Assessor’s comment
Assessor's overall comments on pharmacokinetics in special populations
2.1.10. Interactions
•
In vitro
Assessor’s comment
•
In vivo
Assessor’s comment
Assessor's overall comments on Interactions
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2.1.11. Exposure relevant for safety evaluation
Assessor’s comment
2.1.12. Assessor’s overall conclusions on pharmacokinetics
2.2. Pharmacodynamics
2.2.1. Introduction
2.2.2. Mechanism of action
Assessor’s comment
2.2.3. Primary pharmacology
Assessor’s comment
2.2.4. Secondary pharmacology
Assessor’s comment
2.2.5. Relationship between plasma concentration and effect
Assessor’s comment
2.2.6. Pharmacodynamic interactions with other medicinal products or
substances
Assessor’s comment
2.2.7. Genetic differences in PD response
Assessor’s comment
2.2.8. Assessor’s overall conclusion on pharmacodynamics
3. Clinical efficacy
3.1. Introduction
Example table for study details:
Study
ID
No. of
study
centres
/
locations
Design
Study
Posology
Study
Objective
Subjs by
arm
entered/
compl.
Duration
Gender
M/F
Median
Age
Diagnosis
Incl.
criteria
Primary
Endpoint
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3.2. Dose-response studies and main clinical studies
Assessor’s comment
3.3. Dose response study(ies)
Assessor’s comment
3.4. 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
•
Blinding (masking)
Assessor’s comment
•
Statistical methods
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Rev03.13
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Results
•
Participant flow
(Use and amend as appropriate)
Assessed for
Analysis Followup
Allocatio
n
Enrolmen
t
Eligibility (n=…)
•
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=..)
Lost to follow-up; give
reasons (n=..)
Discontinued
intervention; give
reasons (n=..)
Analysed (n..)
Excluded from analysis;
give reasons (n=..)
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=..)
Analysed (n..)
Excluded from analysis;
give reasons (n=..)
Recruitment
Assessor’s comment
•
Conduct of the study
Assessor’s comment
•
Baseline data
Assessor’s comment
•
Numbers analysed
Assessor’s comment
•
Outcomes and estimation
Assessor’s comment
•
Ancillary analyses
Assessor’s comment
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Rev03.13
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•
Summary of main efficacy results
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:
<time>
Duration of Run-in phase:
<time> <not applicable>
Duration of Extension phase:
<time> <not applicable>
Hypothesis
<Superiority> < Equivalence> <Non-inferiority> <Exploratory: specify>
Treatments groups
<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
<date>
<label>
<free text>
<label>
<free text>
<group descriptor>
<group descriptor>
Endpoints and
definitions
Database lock
Results and Analysis
Analysis description
Primary Analysis
Analysis population
and time point
description
Descriptive statistics
and estimate
variability
<Intent to treat> <Per protocol> <other: specify>
<time point>
Treatment group
Number of
subject
<endpoint>
(<statistic>)
<variability
statistic>
<group
descriptor>
<group
descriptor>
<group
descriptor>
<n>
<n>
<n>
<point
estimate>
<point
estimate>
<point
estimate>
<variability>
<variability>
<variability>
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Rev03.13
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<endpoint>
(<statistic>)
<variability
statistic>
<endpoint>
(<statistic>)
<variability
statistic>
Effect estimate per
comparison
<Co->Primary
endpoint
<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: >
3.5. Clinical studies in special populations
Assessor’s comment
3.6. Analysis performed across trials (pooled analyses AND meta-analysis)
Assessor’s comment
3.7. Supportive study(ies)
Assessor’s comment
3.8. Assessor’s overall conclusions on clinical efficacy
Discussion on clinical efficacy
Design and conduct of clinical studies
Efficacy data and additional analyses
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Rev03.13
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Conclusions on clinical efficacy
4. Clinical safety
4.1. Introduction
Assessor’s comment
4.2. Patient exposure
Example of a table: Patient exposure (cut off)
Patients enrolled
Patients exposed
Patients exposed
Patients with
to the proposed
long term*
dose range
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
4.3. Adverse events
Assessor’s comment
4.4. Serious adverse events and deaths
Assessor’s comment
4.5. Laboratory findings
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
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Rev03.13
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Assessor’s comment
4.6. Safety in special populations
Assessor’s comment
4.7. Immunological events
Assessor’s comment
4.8. Safety related to drug-drug interactions and other interactions
Assessor’s comment
4.9. Discontinuation due to AES
Assessor’s comment
4.10. Post marketing experience
Assessor’s comment
4.11. Assessor’s overall conclusions on clinical safety
Discussion on clinical safety
Conclusions on clinical safety
5. Pharmacovigilance
5.1. 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 (Co)Rapporteur considers that the Pharmacovigilance system 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 (Co) Rapporteur considers that the Pharmacovigilance system 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 CHMP 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>
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Rev03.13
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Assessor’s comment
5.2. Risk management plan
Issues and/or concerns for consideration by the PRAC Rapporteur when assessing the RMP:
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Clinical aspects – Extension of Indication
Rev03.13
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6. List of references
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Clinical aspects – Extension of Indication
Rev03.13
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7. List of questions as proposed by the <Co->rapporteur
Clinical aspects
Major objections
Pharmacokinetics
Pharmacodynamics
Efficacy
Safety
Pharmacovigilance system
Risk management plan
Other concerns
Pharmacokinetics
Pharmacodynamics
Efficacy
Safety
Pharmacovigilance system
Risk management plan
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Clinical aspects – Extension of Indication
Rev03.13
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8. Recommended conditions for marketing authorisation and
product information
User Consultation
<Invented name>
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Rev03.13
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