December 2011
CMDh/203/2005
Decentralised Procedure
RMS Day 70 Preliminary Assessment Report
NON-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>
1/10
Day 70-PrAR-NC
TABLE OF CONTENTS
I.
INTRODUCTION ..................................................................................................................................4
I.1
Type of application and aspects on development ................................................................................4
I.2
GLP aspects ............................................................................................................................................4
II.
PHARMACOLOGY ..............................................................................................................................4
II.1
Primary pharmacodynamics .................................................................................................................4
II.2
Secondary pharmacodynamics .............................................................................................................4
II.3
Safety pharmacology ..............................................................................................................................4
II.4
Pharmacodynamic drug interactions ...................................................................................................4
II.5
Assessor’s overall conclusions on pharmacology.................................................................................4
III.
PHARMACOKINETICS ......................................................................................................................5
III.1 Methods of analysis ................................................................................................................................5
III.2 Absorption...............................................................................................................................................5
III.3 Distribution .............................................................................................................................................5
III.4 Metabolism..............................................................................................................................................5
III.5 Excretion .................................................................................................................................................5
III.6 Pharmacokinetic drug interactions ......................................................................................................6
III.7 Other pharmacokinetic studies .............................................................................................................6
III.8 Assessor’s overall conclusions on pharmacokinetics...........................................................................6
IV.
TOXICOLOGY ......................................................................................................................................6
IV.1 Single dose toxicity .................................................................................................................................6
IV.2 Repeat-dose toxicity ...............................................................................................................................6
IV.3 Genotoxicity ............................................................................................................................................7
IV.4 Carcinogenicity .......................................................................................................................................7
IV.4.1
Long-term studies ..........................................................................................................................7
IV.4.2
Short or medium-term studies......................................................................................................8
IV.4.3
Other studies ..................................................................................................................................8
IV.5 Reproductive and developmental toxicity ............................................................................................8
IV.5.1
Fertility and early embryonic development ................................................................................8
IV.5.2
Embryo-fœtal development...........................................................................................................8
IV.5.3
Prenatal and postnatal development, including maternal function ..........................................8
IV.5.4
Studies in which the offspring (juvenile animals) are dosed and/or further evaluated ..........8
IV.6 Local tolerance........................................................................................................................................8
IV.7 Other toxicity studies .............................................................................................................................9
IV.7.1
Antigenicity ....................................................................................................................................9
IV.7.2
Immunotoxicity ..............................................................................................................................9
IV.7.3
Dependence ....................................................................................................................................9
IV.7.4
Metabolites .....................................................................................................................................9
IV.7.5
Studies on impurities .....................................................................................................................9
IV.7.6
Other studies ..................................................................................................................................9
IV.8 Ecotoxicity/environmental risk assessment..........................................................................................9
IV.9 Assessor’s overall conclusions on toxicology........................................................................................9
V.
LIST OF QUESTIONS AS PROPOSED BY RMS ...........................................................................10
VI.
RECOMMENDED CONDITIONS FOR MARKETING AUTHORISATION AND PRODUCT
INFORMATION ...............................................................................................................................................10
<Invented name>, <Procedure number>
2/10
Day 70-PrAR-NC
LIST OF ABBREVIATIONS
<Invented name>, <Procedure number>
3/10
Day 70-PrAR-NC
NON CLINICAL CRITICAL ASSESSMENT
I.
INTRODUCTION
I.1
Type of application and aspects on development
I.2
GLP aspects
II.
PHARMACOLOGY

Brief summary
Assessor’s comment

Physical chemistry
Structure of the active substance (insert structure)
Site of labelling (see structure)
Isomerism
Molecular weight
Solubility in water
Pka
Distribution coefficient
Solubility in other solvents
Stability
Possible chirality and its consequences
Assessor’s comment
II.1
Primary pharmacodynamics
Assessor’s comment
II.2
Secondary pharmacodynamics
Assessor’s comment
II.3
Safety pharmacology
Assessor’s comment
II.4
Pharmacodynamic drug interactions
Assessor’s comment
II.5
Assessor’s overall conclusions on pharmacology
<Invented name>, <Procedure number>
4/10
Day 70-PrAR-NC
III.
PHARMACOKINETICS

Pharmacokinetic studies
Assessor’s comment
III.1
Methods of analysis
Assessor’s comment
III.2
Absorption
Examples of tables to tabulate absorption data.
Study ID
Species
N
Dose
(mg/kg)
Route
Anal.
Cmax
()
Tmax
()
AUC
()
A
B
Study
ID
A
Species
N
Dose
(mg/kg)
Route
Anal.
T½,el
()
Vd
()
Clt
()
F
(%)
Recovery
(% dose)
Time
(h)
B
Re a)
Re b)
Assessor’s comment
III.3
Distribution
Assessor’s comment
III.4
Metabolism
Assessor’s comment
III.5
Excretion
Example of a table to tabulate excretion data
Species
N
Dose
(mg/kg)
Route
Anal.
Urine
(% dose)
±
<Invented name>, <Procedure number>
Faeces
(% dose)
±
5/10
Bile
(% dose)
±
±
±
Day 70-PrAR-NC
±
±
±
±
±
Assessor’s comment
III.6
Pharmacokinetic drug interactions
Assessor’s comment
III.7
Other pharmacokinetic studies
Assessor’s comment
III.8
Assessor’s overall conclusions on pharmacokinetics
IV.
TOXICOLOGY
IV.1
Single dose toxicity
Example of a table for single dose toxicity studies:
Study ID
Species/
Sex/Number/
Group
Dose/Route
Approx. lethal dose
/ observed max
non-lethal dose
Major findings
Assessor’s comment
IV.2
Repeat-dose toxicity
Example of a table to show repeat-dose toxicity studies:
Study ID
Species/Sex/
Number/Group
Dose/Route
Duration
NOEL/ NOAEL Major findings
(mg/kg/day)
Assessor’s comment

Toxicokinetics
Example of a table to show toxicokinetic studies:
<Invented name>, <Procedure number>
6/10
Day 70-PrAR-NC
Study
Daily Dose
(/)
Animal AUC
(ng.h/ml)
♂
Animal:Human
XXX
Exposure Multiple
♂
♀
♀
Assessor’s comment

Interspecies comparison
Example of a table to compare the exposure in the animal studies with the clinical exposure:
Study
Daily Dose
(/)
Animal AUC
(ng.h/ml)
♂
♀
Cmax
♂
T½
♀
♂
♀
Assessor’s comment
IV.3
Genotoxicity
Example table of the overview of genotoxicity studies:
Type of test/Study
ID/GLP
Gene mutations in
bacteria
Gene mutations in
mammalian cells
Chromosomal
aberrations in vivo
Test system
Concentrations/
Concentration range/
Metabolising system
Salmonella strains
Results
Positive/negative/equivocal
+/- S9
CHO-cells,
+/- S9
HGPRT-locus
Mouse, micronuclei
+/- S9
in bone marrow
Assessor’s comment
IV.4
Carcinogenicity
IV.4.1
Long-term studies
Example table of the overview of carcinogenicity studies performed
Study ID
/GLP
Dose/Route
Exposure
(AUC)
Species/No. of animals
Major findings
Example table of tumour findings in Study xx
Tumour findings
Control
Male
<Invented name>, <Procedure number>
Low dose
Mid dose
7/10
High dose
Day 70-PrAR-NC
Female
Assessor’s comment
IV.4.2
Short or medium-term studies
Assessor’s comment
IV.4.3
Other studies
Assessor’s comment
IV.5
Reproductive and developmental toxicity
Example summary table of the performed studies.
Study type/
Study ID / GLP
Species;
Number
Female/ group
Route &
dose
Dosing
period
Major findings
NOAEL
(mg/kg
&AUC)
Male fertility
Female fertility
Embryo- foetal
development
Peri & postnatal
F0
F1
Assessor’s comment
IV.5.1
Fertility and early embryonic development
Assessor’s comment
IV.5.2
Embryo- foetal development
Assessor’s comment
IV.5.3
Prenatal and postnatal development, including maternal function
Assessor’s comment
IV.5.4
Studies in which the offspring (juvenile animals) are dosed and/or further evaluated
Assessor’s comment
IV.6
Local tolerance
Assessor’s comment
<Invented name>, <Procedure number>
8/10
Day 70-PrAR-NC
IV.7
Other toxicity studies
Assessor’s comment
IV.7.1
Antigenicity
Assessor’s comment
IV.7.2
Immunotoxicity
Assessor’s comment
IV.7.3
Dependence
Assessor’s comment
IV.7.4
Metabolites
Assessor’s comment
IV.7.5
Studies on impurities
Assessor’s comment
IV.7.6
Other studies
Assessor’s comment
IV.8
Ecotoxicity/environmental risk assessment
Assessor’s comment
IV.9
Assessor’s overall conclusions on toxicology
Assessor’s comment
<Invented name>, <Procedure number>
9/10
Day 70-PrAR-NC
V.
LIST OF QUESTIONS AS PROPOSED BY RMS
Non-clinical aspects
Potential Serious Risks to Public Health
Pharmacology
Pharmacokinetics
Toxicology
Points for clarification
Pharmacology
Pharmacokinetics
Toxicology
VI.
RECOMMENDED CONDITIONS FOR MARKETING
AUTHORISATION AND PRODUCT INFORMATION
<Invented name>, <Procedure number>
10/10
Day 70-PrAR-NC