RAMEEZ PERVAIZ

MODULE 4: NON-CLINICAL STUDY COMPARISON –

SMALL MOLECULES AND BIOLOGICS

Common Technical Document & Module 4 Nonclinical Studies: Biologics v. Small Molecules

OUTLINE

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

ANIMAL SPECIES

SAFETY PHARMACOLOGY

A core battery of safety pharmacology studies to assess vital organs risk:

SAFETY PHARMACOLOGY

Small Molecules

Biologics

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

CARCINOGENICITY – SMALL MOLECULES

2 year rat study

Models of carcinogene

sis

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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