Preclinical Safety Evaluation of Biotechnology-Derived ...

kettleitchyBiotechnology

Dec 5, 2012 (4 years and 6 months ago)

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Regulatory Issues for CROs
Evaluation of

Biotechnology
-
Derived
Pharmaceuticals

K.K. Tripathi, PhD

Adviser and Member Secretary, RCGM

Department of Biotechnology

Ministry of S&T, GOI

kkt@dbt.nic.in

The views expressed in this presentation are those of the author and they have nothing to do with the
regulatory
authoriries

in place and GOI


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Structure of the Presentation

Basics



Defining Biotech Medicines, Biopharmaceuticals,
Biogenerics & Biosimilars !!!



EU and USA scenario and perspectives


Indian Viewpoint

Regulation



EU and USA



India

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What are Biopharmaceuticals? Compared to drug


Biopharma industry
-
25 yrs old with >350 marketed
products.


Term widely used but hardly defined by users


Over 4 million entries on Google search


Involves use of biotechnology and pharmaceutical
compared to drug


Antsense oligos, RNAi, synthetic peptides and other
products mimic biopharma as well drug

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Worldwide off Patent Biotech Medicines often
referred as

Generic Biophamaceuticals, (USA)

Biogenerics, (USA)

Follow
-
on Biologics, (USA)

Biosimilars, (EU) (rDNA & hybridoma derived)

Off Patent Biologicals, (All)


and so on ,,,,,,,,,,,,,,,

Definition is Market and Commerce based

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Biotech medicines often
replace or supplement a
natural protein produced by
the body, satisfying medical
needs previously unmet by
chemical medicines

What Are Biotech Medicines?



More than 325 million patients worldwide have been
helped by biotech medicines


More than 50% of medicines in development are
biotech medicines

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EU View: Biosimilars are not generic pharmaceuticals


Generics are clinically identical to their reference products


Biosimilars can never be identical to their reference products

􀂃
Due to the complexity & variability of a biological, the quality
profile is determined by the manufacturing process


'the product is the process'

􀂃
Differences in process are inevitable between different
manufacturers


minor process differences can lead to marked differences in
clinical profile

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Biosimilars are similar, not identical, to original
biotech products

Biosimilars are similar…….

….
Not Identical

Different cell lines

Different mfg process

Small differences in substrate and mfg process may affect
patient safety and clinical efficacy of the product

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Impact of small differences among biotech products
on efficacy and safety is unpredictable



Safety and efficacy can differ significantly with small
changes in

protein biophysical characteristics or

formulation of the drug produc


Long term safety profile of biosimilars has yet to be
established


Prescribers and patients should be aware of this to
ensure appropriate introduction into clinical practice


Need to recognize safety and efficacy issue in both
approval process and introduction into clinical
practice of biosimilars

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INDIAN Scenario



No Biosimilar, only Biogeneric as in USA


No Guidelines



Schedule Y of Drugs and Cosmetics Act



EMEA/ICH Guidelines



More than 20 products approved so far


Guidelines to be put in place soon

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Biogeneric products approved so far in India

Sal No

1

2

3

4

5

6

7


8

9


10

11

12

Molecule

Human insulin

Erythropoietin

Hepatitis B vaccine

Human growth hormone

Interleukin 2

Interleukin 11

Granulocyte Colony
Stimulating Factor

Colony Stimulating Factor

Interferon2Alpha

Interferon 2Beta

Interferons

Gamma

Streptokinase


Sal No

13


14

15


16

17


18


19


20

Molecule

Tissue
Plasminogen

Activator

Blood factor VIII

Follicle stimulating
hormone

Teriparatide

(
Forteo
)

Drerecogin

(
Xigris
) alpha

Platelet Derived Growth
factor (PDGF)

Epidermal Growth factor
(EGF)

Eptacogalpha (r
-
F VIIa) r
-
coagulation factor

Refer DBT Website:
www.igmoris.nic.in

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The Primary Goals of Preclinical
Safety Evaluation are


Identify an initial safe dose and subsequent
dose escalation schemes in humans


Identify potential target organs for toxicity and
for reversibility


Identify safety parameters for clinical
monitoring

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The Test Materials


Monoclonal antibodies, Cytokines, Growth factors,
Vaccines, Fusion proteins, Hormones, Chemically
synthesized peptides, Enzymes, Plasma derived
products, Receptors, Oligonucleotides, proteins
extracted from human tissue, biotransformed drugs
with small molecular weight as generic products of
Pharma, and Guess what more !!!!!!

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The Test Substances


Investigational new drug or new entities


Biologically similar to an already tested
and used drug or molecule as a biologic



What to term it Biogeneric? Biosimilar?
Or !!!!!

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Comparability


Evaluated on the basis of biochemical and
biological characterization (i.e., identity,
purity, stability, and potency).


In some cases, additional studies may be
needed (i.e., pharmacokinetics, pharmaco
-
dynamics and / or safety).

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Preclinical Safety Testing
Requirements



Selection

of

the

relevant

animal

species
;



Age
;



Physiological

state
;



Dose,

route

of

administration,

and

treatment

regimen
;

and



Stability

of

the

test

material

under

the

conditions

of

use
.


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Approaches


Conventional

approaches

to

toxicity

testing

of

pharmaceuticals

may

not

be

appropriate

due

to

the

unique

and

diverse

structural

and

biological

properties
.



This

includes

species

specificity,

immunogenicity,

and

unpredicted

activities
.


Biological

activity

may

be

evaluated

using

in

vitro

assays
.


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Receptor / Epitope Distribution


Knowledge

of

receptor/

epitope

distribution

can

provide

greater

understanding

of

potential

in

vivo

toxicity

.


Relevant

animal

species

for

testing

of

monoclonal

antibodies

are

those

that

express

the

desired

epitope

and

demonstrate

a

similar

tissue

cross
-
reactivity

profile

as

for

human

tissues
.



An

animal

species

that

does

not

express

the

desired

epitope

may

still

be

of

some

relevance

for

assessing

toxicity

if

comparable

unintentional

tissue

cross

reactivity

to

humans

is

demonstrated
.


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Species to be Studied


Safety

evaluation

programs

should

normally

include

two

relevant

species
.



one

relevant

species

may

suffice

(e
.
g
.
,

when

only

one

relevant

species

can

be

identified

or

where

the

biological

activity

of

the

biopharmaceutical

is

well

understood)
.



In

addition,

even

where

two

species

may

be

necessary

to

characterize

toxicity

in

short

term

studies,

it

may

be

possible

to

justify

the

use

of

only

one

species

for

subsequent

long
-
term

toxicity

studies

(e
.
g
.
,

if

the

toxicity

profile

in

the

two

species

is

comparable

in

the

short

term)
.


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When No Relevant

Species Exists


The

use

of

relevant

transgenic

animals

expressing

the

human

receptor

or

the

use

of

homologous

proteins

should

be

considered
.



Pharmacological

mechanism(s)

may

differ

between

the

homologous

form

and

the

product

intended

for

clinical

use
.



Where

it

is

not

possible

to

use

transgenic

animal

models

or

homologous

proteins

evaluation

in

a

single

species,

e
.
g
.
,

a

repeated

dose

toxicity

study

of

<

14

days

duration

that

includes

an

evaluation

of

important

functional

endpoints

(e
.
g
.
,

cardiovascular

and

respiratory)
.



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Administration / Dose Selection


The

route

and

frequency

of

administration

as

close

as

possible

to

proposed

clinical

use
.



Pharmacokinetics

and

bioavailability

of

the

product

in

the

species

being

used
.



Effects

of

volume,

concentration,

formulation,

and

site

of

administration
.



The

use

of

routes

of

administration

other

than

those

used

clinically

may

be

acceptable

if

the

route

must

be

modified

due

to

limited

bioavailability,

limitations

due

to

the

route

of

administration,

or

to

size/physiology

of

the

animal

species
.



Two

routes

otherwise

is

not

required
.


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Dosage levels


Dosage

levels

should

be

selected

to

provide

information

on

a

dose
-
response

relationship,


Include

a

toxic

dose

and

a

no

observed

adverse

effect

level

(NOAEL)
.



Products

with

little

to

no

toxicity,

it

may

not

be

possible

to

define

a

specific

maximum

dose
.



In

these

cases,

a

scientific

justification

of

the

rationale

for

the

dose

selection

and

projected

multiples

of

human

exposure

should

be

provided
.



Where

a

product

has

a

lower

affinity

to

or

potency

in

the

cells

of

the

selected

species

than

in

human

cells,

testing

of

higher

doses

may

be

important
.


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Immunogenicity




Antibody Formation In Humans




Safety Pharmacology




Pharmacokinetic studies




Single Dose Toxicity Studies




Repeated Dose Toxicity Studies




Immunotoxicity Studies




Reproductive Performance and Developmental
Toxicity Studies




Genotoxicity Studies




Carcinogenicity Studies

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Carcinogenicity Studies 2


With

some

biopharmaceuticals,

there

is

a

potential

concern

about

accumulation

of

spontaneously

mutated

cells

(e
.
g
.
,

via

facilitating

a

selective

advantage

of

proliferation)

leading

to

carcinogenicity
.



The

standard

battery

of

genotoxicity

tests

is

not

designed

to

detect

these

conditions
.



Alternative

in

vitro

or

in

vivo

models

to

address

such

concerns

may

have

to

be

developed

and

evaluated
.


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