ctd module 4 presentation (1)
TRANSCRIPT
COMMON TECHNICAL DOCUMENT (CTD)
• Dossier format for technical information
• Adopted by Europe, Japan and USA through the International Conference on Harmonisation (ICH)
• Support regulatory review and product registration for marketing
Source: ICH.org Accessed: October 6 2015
MODULE 4: NON-CLINICAL
• Module 4: Compiles product’s nonclinical results
• 4.1: Table of Contents• 4.2: Study Reports• Pharmacological,
pharmacokinetic and toxicological evaluation of pharmaceuticals
Identify safety doses and plausible dose escalation in humans
Potential target organs and toxicities Reversible and
irreversibleClinical safety and
possible monitoring parameters
MODULE 4: NON-CLINICAL
• Animal Species
• Acute, Sub-Chronic and Chronic toxicity Studies
• Reproductive Toxicity
• Local Tolerance Study
COMPARISON OVERVIEW
= Biologics
= Both = Small Molecules
Both pharmaceuticals must show a dose-response relationship to determine: High dose No Observed Adverse Event level (NOAEL)
TOXICITY STUDIES
Small Molecules Use the Maximum Tolerated Dose (MTD):
Standard limit: 1000 mg/kg/day 10-fold mean margin exposure to clinical exposure Cannot exceed 1 g/day
MTD or usual limit doesn’t work: 2000 mg/kg/day Limit by 10-fold margin exposure Maximum Feasible Dose (MFD)
Biologics may not have MTD determine high dose: Maximum intended dose in species 10-fold exposure multiple over the maximum exposure in
the study Scientifically justify selected doseNo in vivo/in vitro Pharmacodynamic (PD) endpoints:
Pharmacokinetic data In vitro binding data Pharmalogical
TOXICITY STUDIES - BIOLOGICS
SMALL MOLECULES
RodentsNonrode
ntsClinical
Trials
2 weeks 2 weeks 2 weeks
Same as trial
Same as trial
2 weeks- 6 months
6 months 9 months > 6 months
BIOLOGICS
Average: 1-3 months
Chronic: 6 months
Short-term < 7
days Up to 7 weeks
DURATION: REPEAT-DOSE STUDY
Anticancer in Both: 3 months
TISSUE CROSSREACTIVITY STUDY
Monoclonal Antibodies(mAbs): Majority of biologics in market
Development Progress: MAbs become more humanized Confirm relevant species for toxicology assessment
Tissue crossreactivity (TCR) Studies: In vitro tissue assay In vitro-in vivo functional assays
Toxicology study showing compound’s effect on
restricted body portions
LOCAL TOLERANCE STUDY
Small molecules one
single-dose single
species is satisfactory
Incorporated into
Toxicology study
Biologics:
Some cases: Single/repeat-
dose study adequate to
display local tolerance
Carcinogenicity – identify tumorigenic potential Carcinogenic concerns:
6 months of therapy Intermittent therapy with re-exposure potential Mechanism of action Class effect Toxicity study results Genotoxicity Patient population & indication Systemic exposure extent
Dermatological Ocular
CARCINOGENICITY
Bioassays are not relevant Cellular proliferation potential in vitro receptor
analysis Positive in vitro data Animal models
Long-term repeated dose rodent study
Replacement therapyCircumstances for concern:
Different biological effect than natural counterpart Significant structure modification Increasing concentration over physiological level
CARCINOGENICITY - BIOLOGICS
Biologics: unless risk seen Don’t perform study Larger biologics do not interact with chromosomal material
Small Molecules Perform battery to determine risk:
GENOTOXICITY
Small MoleculesEmphasis on
immunotoxicity
Toxicity studies yield immune-mediated ADRs further immunotoxicity studies
28-day repeat-dose
rodent study
BiologicsEmphasis on
immunogenicityWant to characterize
anti-drug-antibodies (ADA) effects: Influence on PD and markers Altered absorption or
clearance Immune-mediated reactions
anaphylaxis, vasculitis Repeat-Dose Toxicity -
obtaining ADA samples during observation
IMMUNOTOXICITY
Sample size: 16-20 litters Same species & size as other Toxicology studies Combination studies suggested:
Fertility and early-embryonic development Prenatal and postnatal development (PPND) Embryo-fetal development (EFD)
Biologics: Nonhuman Primates (NHP) as only relevant species Known drug class toxicity May not have to perform
REPRODUCTIVE TOXICITY
Fertility and Early-embryonic Development
1:1 mating ratio identify offspring lineage
Repeated-Dose study for 1 month
Biologics: Should be mice or rats NHP hard mating
process observe reproductive tracts
Embryo-Fetal Development (EFD)
From implantation to hard palate closure
2 species: rodents and nonrodents
Rodent: rats preferred 50% for visceral changes 50% for skeletal changes
Nonrodents: rabbits preferred 100% observed for
visceral & skeletal changes
REPRODUCTIVE TOXICITY
EFD- BIOLOGICS
High molecular weight proteins cannot cross placenta via diffusion Monoclonal Antibodies(mAbs) Neonatal Fc
receptor(FcRn): FcRn: transporter for heavy mAbs Varies across species
NHPs & human low IgG placental transfer in organogenesis Standard EF studies Cannot perform
NHPs only secrete IgG in initial milking: Maternal dosing is irrelevant.
Rodents IgG crosses the yolk earlier: Dose dams for 9 days during lactation
One species: rats preferredFemales exposed from implantation to
lactation One male & female from each litter
assess developmental competency Biologics: Yield 6-7 offsprings at Day 7 for developmental competency
PRENATAL AND POSTNATAL DEVELOPMENT
ENHANCED PRENATAL & POSTNATAL DEVELOPMENT (ePPND)
NHPs in Biologics Gestation Day 20 to BirthMinimum offsprings follow-up: 1 month Immune function adverse events
minimum 3-6 mo. observation
BiologicsAbsorption, Distribution
& Excretion dataMetabolism not
necessary No biotransformation studies
Single, multiple-dose & tissue distribution studies No mass balance test
Determine plasma protein binding & anti-drug-antibody formation
Small MoleculesAbsorption, Distribution,
Metabolism & Excretion data
Metabolism: characterization of pathway & metabolites
Single, multiple-dose, tissue distribution & mass balance studies
In vitro metabolic & plasma protein binding studies
PHARMACOKINETICS
D i x i t R , I c i e k L A , M c K e e v e r K , Ry a n P C . C h a l l e n g e s o f g e n e r a l s a f e t y e v a l u a t i o n s o f b i o l o g i c s c o m p a r e d t o s m a l l m o l e c u l e p h a r m a c e u t i c a l s i n a n i m a l m o d e l s . E x p e r t O p i n D r u g D i s c o v. 2 0 1 0 J a n ; 5 ( 1 ) : 7 9 - 9 4 . d o i : 1 0 . 1 5 1 7 / 1 7 4 6 0 4 4 0 9 0 3 4 4 3 4 1 0 . A c c e s s e d : O c t o b e r 0 6 , 2 0 1 5 .F o o d a n d D r u g A d m i n i s t r a t i o n C e n t e r f o r D r u g E v a l u a t i o n a n d R e s e a r c h . G u i d a n c e f o r I n d u s t r y : M 3 ( R 2 ) N o n c l i n i c a l S a f e t y S t u d i e s f o r t h e C o n d u c t o f H u m a n C l i n i c a l Tr i a l s a n d M a r k e t i n g A u t h o r i z a t i o n f o r P h a r m a c e u t i c a l s . ( J a n u a r y 2 0 1 0 ) . R o c k v i l l e , M D . A c c e s s e d o n O c t o b e r 2 , 2 0 1 5 .F o o d a n d D r u g A d m i n i s t r a t i o n C e n t e r f o r D r u g E v a l u a t i o n a n d R e s e a r c h . G u i d a n c e f o r I n d u s t r y : S 6 P r e c l i n i c a l S a f e t y E v a l u a t i o n o f B i o t e c h n o l o g y - D e r i v e d P h a r m a c e u t i c a l s . ( J u l y 1 9 9 7 ) . R o c k v i l l e , M D . A c c e s s e d o n O c t o b e r 5 , 2 0 1 5 . F o o d a n d D r u g A d m i n i s t r a t i o n C e n t e r f o r D r u g E v a l u a t i o n a n d R e s e a r c h . G u i d a n c e f o r I n d u s t r y : S 6 A d d e n d u m t o P r e c l i n i c a l S a f e t y E v a l u a t i o n o f B i o t e c h n o l o g y - D e r i v e d P h a r m a c e u t i c a l s . ( M a y 1 7 , 2 0 1 2 ) . R o c k v i l l e , M D . A c c e s s e d o n O c t o b e r 5 , 2 0 1 5 . F o o d a n d D r u g A d m i n i s t r a t i o n C e n t e r f o r D r u g E v a l u a t i o n a n d R e s e a r c h . G u i d a n c e f o r I n d u s t r y : S 1 A T h e N e e d f o r L o n g - t e r m R o d e n t C a r c i n o g e n i c i t y S t u d i e s o f P h a r m a c e u t i c a l s . ( M a r c h 1 , 1 9 9 6 ) . R o c k v i l l e , M D . A c c e s s e d o n O c t o b e r 5 , 2 0 1 5 .F o o d a n d D r u g A d m i n i s t r a t i o n C e n t e r f o r D r u g E v a l u a t i o n a n d R e s e a r c h . G u i d a n c e f o r I n d u s t r y : S 2 A S p e c i f i c A s p e c t s o f R e g u l a t o r y G e n o t o x i c i t y Te s t s f o r P h a r m a c e u t i c a l s . ( A p r i l 1 1 9 9 6 ) . R o c k v i l l e , M D . A c c e s s e d o n O c t o b e r 5 , 2 0 1 5 . F o o d a n d D r u g A d m i n i s t r a t i o n C e n t e r f o r D r u g E v a l u a t i o n a n d R e s e a r c h . G u i d a n c e f o r I n d u s t r y : S 2 B G e n o t o x i c i t y : A S t a n d a r d B a t t e r y f o r G e n o t o x i c i t y Te s t i n g o f P h a r m a c e u t i c a l s . ( N o v e m b e r 2 1 1 9 9 7 ) . R o c k v i l l e , M D . A c c e s s e d o n O c t o b e r 5 , 2 0 1 5 . F o o d a n d D r u g A d m i n i s t r a t i o n C e n t e r f o r D r u g E v a l u a t i o n a n d R e s e a r c h . G u i d a n c e f o r I n d u s t r y : S 2 ( R 1 ) G e n o t o x i c i t y Te s t i n g a n d D a t a I n t e r p r e t a t i o n f o r P h a r m a c e u t i c a l s I n t e n d e d f o r H u m a n U s e . ( M a y 1 7 , 2 0 1 2 ) . R o c k v i l l e , M D . A c c e s s e d o n O c t o b e r 6 , 2 0 1 5 . F o o d a n d D r u g A d m i n i s t r a t i o n C e n t e r f o r D r u g E v a l u a t i o n a n d R e s e a r c h . G u i d a n c e f o r I n d u s t r y : S 7 A S a f e t y P h a r m a c o l o g y S t u d i e s f o r H u m a n P h a r m a c e u t i c a l s . ( J u l y 0 1 , 2 0 0 1 ) . R o c k v i l l e , M D . A c c e s s e d o n O c t o b e r 6 , 2 0 1 5 . F o o d a n d D r u g A d m i n i s t r a t i o n C e n t e r f o r D r u g E v a l u a t i o n a n d R e s e a r c h . G u i d a n c e f o r I n d u s t r y : S 8 I m m u n o t o x i c i t y S t u d i e s f o r H u m a n P h a r m a c e u t i c a l s . ( A p r i l 2 1 , 2 0 0 6 ) . R o c k v i l l e , M D . A c c e s s e d o n O c t o b e r 6 , 2 0 1 5 . F o o d a n d D r u g A d m i n i s t r a t i o n C e n t e r f o r D r u g E v a l u a t i o n a n d R e s e a r c h . G u i d a n c e f o r I n d u s t r y : S 9 N o n c l i n i c a l E v a l u a t i o n f o r A n t i c a n c e r P h a r m a c e u t i c a l s . ( M a r c h 0 5 , 2 0 1 0 ) . R o c k v i l l e , M D . A c c e s s e d o n O c o b e r 6 , 2 0 1 5 .
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