Transcript Safety Sciences

Safety Sciences Role in
Pharmaceutical Development
Safety Sciences Functional
Objectives and Responsibilities
Discovery
Stage
Gates
ESD
SDS
SAN
ED
LD
POP
CS
FD
PreP-1 P-2
Clinical
LAN
CAN
P-3
R2D2
IND
Documents
POP
pCAN
CAN
Target/
Benchmark
Strategy
SSLJ
Responsibility
TAL
TAL+
In.Sci
ETOSA,
LBR
TAL+Path
+In. Sci
TOT,
TI
Path+
ECMT
Rep.+Gen
eral Tox+
In.Sci
ECMT Rep + TAL
NDA
Alignment of Safety Sciences
Activities with Drug Discovery/
Development Stages (SDS)
ESD
SDS
CS
LD
SDS
SAN
Safety
Sciences
Objective
POP
POP
Mechanism- or
target based
liabilities
Philosophy
Use model or
protoype to detect
fundamental risks
Capability
Focused in vitro
assays or (limited)
in vivo work in
model; literature
LAN
PreP-1 P-2
Clinical
CAN
P-3
R2D2
IND
NDA
Alignment of Safety Sciences
Activities with Drug Discovery/
Development Stages (LD)
ESD
SDS
CS
LD
PreP-1 P-2
Clinical
LD
SAN
Safety
Sciences
Objective
Philosophy
Capability
POP
LAN
CAN
LAN
Probablilitybased adverse
outcome screen
Generic approach to
reducing attrition by
detecting patterns
previously associated
with adverse outcomes
Toolbox
P-3
R2D2
IND
NDA
Alignment of Safety Sciences
Activities with Drug Discovery/
Development Stages (CS)
ESD
SDS
CS
LD
PreP-1 P-2
Clinical
CS
SAN
POP
LAN
CAN
CAN
Safety
Sciences
Objective
Philosophy
Capability
P-3
R2D2
IND
Issue Resolution
(targeted)
Targeted approach to
integrate concentrationexposure relationships
and past experience into
candidate optimization
Toolbox
Biological
Properties
NDA
Alignment of Safety Sciences
Activities with Drug Discovery/
Development Stages (CAN to FIH)
ESD
SDS
SAN
Safety
Sciences
Objective
Philosophy
Capability
CS
LD
POP
LAN
PreP-1 P-2
Clinical
P-3
R2D2
CAN
CAN
FIH
IND
Position for rapid FIH
support and accurate
bulk estimation; support
introduction into
humans
Identify safe clinical
starting doses and
relevant biomarkers;
Risk Manage
Studies
NDA
Alignment of Safety Sciences
Activities with Drug Discovery/
Development Stages (POC)
ESD
SDS
CS
LD
PreP-1 P-2
Clinical
P-3
POC
SAN
POP
LAN
CAN
R2D2
IND
Safety
Sciences
Objective
Philosophy
Capability
Estimate human
risk
Minimize human risk
until POC is shown
and a reasonable
risk-benefit
comparison can be
made
Studies
NDA
Alignment of Safety Sciences
Activities with Drug Discovery/
Development Stages (FD)
ESD
SDS
SAN
CS
LD
POP
LAN
PreP-1 P-2
Clinical
CAN
P-3
FD
R2D2
IND
Safety
Sciences
Objective
Philosophy
Capability
NDA
Define human
risk
Definitive preclinical
assessments of
relevant human risks
Studies
Alignment of Safety Sciences
Activities with Drug Discovery/
Development Stages (Registration)
ESD
SDS
SAN
CS
LD
POP
LAN
PreP-1 P-2
Clinical
CAN
R2D2
IND
Safety
Sciences
Objective
Philosophy
Capability
P-3
Registration
NDA
Obtain approval
and appropriate
label descriptions
Communicate
risks clearly and
unambiguously;
provide guidance
for detection of
undesired effects
Phase IV
Studies
LJ Safety Sciences Toolbox
(*under development)
Function
Gene Tox
Assay/Tool
Stage
Rank Order
SDS, LD, CS
Ames
Decision Making
SDS, LD, CS
In vitro Micronucleus
Decision Making
SDS, LD, CS
Cerep
Rank Order
LD, CS
HERG
Decision Making
LD, CS
Purkinje
Decision Making
CS
Telemetry*
Decision Making
CS
Safety of Target
Antisense*, Trasgenics, Abs,
Reporter*
Decision Making
SDS
Target Organ/Safety
Margin
Gene Expression (eg. arrays,
PCR)
Rank Order
LD, CS
Protein Modulation
Rank Order
LD, CS
In Vitro Cytotoxicity
Rank Order
LD, CS
Rank Order, Decision
Making
CS
Rank Order
CS
CV/Safety Pharm
DEREK
Utility
In Vivo assays (eg. RF, LBRs,
PK/Discovery studies)
Metabonomics*
1 2
Biological Properties Evaluated
in a Safety Assessment
•
•
•
•
•
•
•
•
Acute Toxicity
Cumulative/ Chronic Toxicity
Teratogenicity
Reproductive Toxicity
Genotoxicity
Local Effects
Carcinogenicity
Pharmacology
Studies Conducted During the
Pre-Clinical Phase
• Genotoxicity
Bacterial Reverse Mutation & Chromsomsal
Aberration
• Safety Pharmacology CV/Respiratory & Behavior
• Acute Toxicity 1 rodent and 1 non-rodent species (may be part of
repeated-dose study)
• Cumulative Toxicity
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–
–
–
1 Rodent and 1 non-rodent Species
< 2 Weeks in humans: 2 Weeks in Tox Studies
Up to 1 Month: 1 Month
Up to 3 Months: 3 Months
Up to 6 Months: 6 Months
> 6 Months: 6 Months Rodent + 9 (12) Months Non-Rodent
Studies Conducted During
Human Clinical Trials
• Phase II (Therapeutic Exploratory)
– Cumulative/Repeat dose
Same as Phase I for all Regulatory Agencies
Schedule-Dependent up to 6 Months
– Embryo-Fetal Development (2 Species)
– Reproductive Tox
– Genotoxicity Additional mammalian mutation/in vivo
clastogenicity
Studies Conducted During
Clinical Trials Continued
• Phase III (Therapeutic Confirmatory)/Pre-NDA
– Complete Reproductive Toxicity Studies
– EU and Japan Trials/Marketing
Up to 3 Months: 6 Months Rodent + 3 Months Non-Rodent
Greater than 6 Months: 6 Months Rodent + 9 (12) Months Non-Rodent
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–
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Support CMC/EU Notification
Begin Carcinogenicity Studies (2 Species)
Complete Safety Pharmacology
Specialized Safety (aged, pediatrics, metabolites)
Studies Conducted Post
Marketing Approval
Phase IV
• Post Marketing Studies
– Clinical studies to extend claims or usage of
new patient population or indication
– To demonstrate manufacturing changes
– To validate surrogate clinical endpoints
required in cases of accelerated approval
Risk Management
• Compound A:
GI: emesis,Hemorrhage
Hematology: Thrombocytopenia,
hyperglycemia, Increase PT
CNS: Convulsions, seizures
Respiration: Rate increased
Fatalities: yes
Would you advance this compound
into Phase 1 healthy volunteers?
• Compound B:
GI: Emesis, loss of appetite
CNS: Tremors, convulsions,
chills, flushing
CV: Tachycardia, arrythmias
Reproduction: Teratogenic
Would you advance this
compound into Phase 1
healthy volunteers?
Risk Management
• Aspirin:
GI: emesis,Hemorrhage
Hematology: Thrombocytopenia,
hyperglycemia, Increase PT
CNS: Convulsions, seizures
Respiration: Rate increased
Fatalities: yes
Risk Management
• Caffeine:
GI: Emesis, loss of appetite
CNS: Tremors, convulsions,
chills, flushing
CV: Tachycardia, arrythmias
Reproduction: Teratogenic
Parameters Evaluated in
Safety studies
• Clinical Observations: General condition and behavior, Food
consumption, Body weights, Ophthalmology, Mortalities
• Clinical Chemistry:
AST
sodium
total protein
albumin
triglycerides
glucose
ALT
potassium
globulin
total cholesterol
A/G ratio
GGT
Alk Phos
calcium
chloride
BUN
creatinine
total bilirubin
Continued…
Parameters Evaluated in
Safety studies
• Hematology:
Hemoglobin (Hg) conc.
RBC volume
WBC (total & Differential)
aPTT
RBC
RBC Hg
platelet count
platelet volume
HCT
reticulocytes
prothrombin time
bone marrow smears
• Urinalysis:
Specific gravity
Protein
volume
sediment
bilirubin
glucose
pH
ketones
Continued…
Parameters Evaluated in
Safety studies
• Necropsy:
– Gross evaluation
– Organ weights
– Microscopic (see list below)
List of organs/tissues evaluated
Gross lesions
Kidney
Liver
Pancreas
Heart
Aorta
Mammary gland
Tongue
Urinary bladder
Salivary gland
Skin/adnexa
Trachea
Continued…
Parameters Evaluated in
Safety studies
List of organs/tissues evaluated
Lung
Spleen
Thymus
Thyroid
Parathyroid
Adrenal
Testis
Epididymis
Prostate
Ovary
Cervix
Uterus
Esophagus Stomach
Duodenum
Ileum
Cecum
Colon
Spinal cord Eye
Bone (sternum)
Joint
Bone Marrow
Optic nerve
Ureter
GALT
Larynx
Lymph nodes
Pituitary
Seminal vesicle
Vagina
Jejunum
Brain
Nerve (peripheral)
Oviduct
Turbinates
Parameters Evaluated in
Embryo-Fetal Development
studies
• Clinical Observations: General condition and behavior,
Food consumption, Body weights, Mortalities
• Laparotomy
– Dams:
Gravid uterine wt.
Corpora lutea
Implantation sites
Early/late resorptions
Dead/live fetuses
Placenta
– Fetus:
Body wt.
Sex
external
Internal
Skeletal
Parameters Evaluated in Fertility
& Early Embryonic
Development studies
• Clinical Observations: General condition and behavior,
Food consumption, Body weights, Estrus cycle, Mortalities
• Females
Corpora lutea
Abortions
Implantation sites
Premature deliveries
• Males
Sperm count and motility from epididymis and vas deferens
Parameters Evaluated in Pre- and
Post-Natal Development studies
• F0-Clinical Observations: General condition and behavior,
Food consumption, Body weights, Lactation, Mortalities
• F0 females: Implantation sites and Gross necropsy
• F1: Pup weights, Appearance, Behavior, external/oral
cavity abnormalities, visual integrity, sexual maturity,
Locomotor activity, Startle response, Water maze, Passive
avoidance and FOB
• F1 Breeding: Estrus cycle, implantation sites and viable
fetuses
• F2: Pup weights, number and sexing and external/oral
abnormalities