127

Regulatory Issues for CROs Evaluation of

Biotechnology-Derived Pharmaceuticals

KK Tripathi PhDKK Tripathi PhDAdviser and Member Secretary RCGMAdviser and Member Secretary RCGM

Department of BiotechnologyDepartment of BiotechnologyMinistry of SampT GOIMinistry of SampT GOI

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

regulatory authoriries in place and GOIregulatory authoriries in place and GOI

227

Structure of the Presentation

Basics

bull Defining Biotech Medicines Biopharmaceuticals Biogenerics amp Biosimilars

bull EU and USA scenario and perspectives

bullIndian Viewpoint

Regulation

bull EU and USA

bull India

327

What are Biopharmaceuticals Compared to drug

bullBiopharma industry-25 yrs old with gt350 marketed products

bullTerm widely used but hardly defined by users

bullOver 4 million entries on Google search

bullInvolves use of biotechnology and pharmaceutical compared to drug

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

427

Worldwide off Patent Biotech Medicines often referred as

Generic Biophamaceuticals (USA)

Biogenerics (USA)

Follow-on Biologics (USA)

Biosimilars (EU) (rDNA amp hybridoma derived)

Off Patent Biologicals (All)

and so on

Definition is Market and Commerce based

527

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

bullMore than 325 million patients worldwide have been helped by biotech medicinesbullMore than 50 of medicines in development are biotech medicines

627

EU View Biosimilars are not generic pharmaceuticalsndashGenerics are clinically identical to their reference productsndashBiosimilars can never be identical to their reference products1048707Due to the complexity amp variability of a biological the quality profile is determined by the manufacturing processndashthe product is the process1048707Differences in process are inevitable between different manufacturersndashminor process differences can lead to marked differences in clinical profile

727

Biosimilars are similar not identical to original biotech products

Biosimilars are similarhelliphellip hellipNot Identical

Different cell lines Different mfg process

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

827

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

Safety and efficacy can differ significantly with small changes in ndashprotein biophysical characteristics or ndashformulation of the drug producLong 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

927

INDIAN Scenario

No Biosimilar only Biogeneric as in USA

No Guidelines

Schedule Y of Drugs and Cosmetics Act

EMEAICH Guidelines

More than 20 products approved so far

Guidelines to be put in place soon

1027

Biogeneric products approved so far in India

Sal No1234567

89

101112

MoleculeHuman insulin Erythropoietin Hepatitis B vaccine Human growth hormoneInterleukin 2Interleukin 11Granulocyte Colony Stimulating FactorColony Stimulating FactorInterferon2AlphaInterferon 2BetaInterferons GammaStreptokinase

Sal No13

1415

1617

18

19

20

MoleculeTissue PlasminogenActivatorBlood factor VIIIFollicle stimulating hormoneTeriparatide (Forteo)Drerecogin (Xigris) alphaPlatelet Derived Growth factor (PDGF)Epidermal Growth factor (EGF)Eptacogalpha (r-F VIIa) r-coagulation factor

Refer DBT Website wwwigmorisnicin

1127

The Primary Goals of Preclinical Safety Evaluation are

bull Identify an initial safe dose and subsequent

dose escalation schemes in humans

bull Identify potential target organs for toxicity and

for reversibility

bull Identify safety parameters for clinical

monitoring

1227

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

1327

The Test Substances

bullInvestigational new drug or new entities

bullBiologically similar to an already tested

and used drug or molecule as a biologic

bull What to term it Biogeneric Biosimilar

Or

1427

Comparability

Evaluated on the basis of biochemical and

biological characterization (ie identity

purity stability and potency)

In some cases additional studies may be

needed (ie pharmacokinetics pharmaco-

dynamics and or safety)

1527

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

1627

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

1727

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

1827

Species to be Studied Safety evaluation programs should normally include two

relevant species

one relevant species may suffice (eg 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 (eg if the toxicity profile in the two species is comparable in the short term)

1927

When No RelevantSpecies 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 eg a repeated dose toxicity study of lt 14 days duration that includes an evaluation of important functional endpoints (eg cardiovascular and respiratory)

2027

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

sizephysiology of the animal species

Two routes otherwise is not required

2127

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

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

327

What are Biopharmaceuticals Compared to drug

bullBiopharma industry-25 yrs old with gt350 marketed products

bullTerm widely used but hardly defined by users

bullOver 4 million entries on Google search

bullInvolves use of biotechnology and pharmaceutical compared to drug

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

427

Worldwide off Patent Biotech Medicines often referred as

Generic Biophamaceuticals (USA)

Biogenerics (USA)

Follow-on Biologics (USA)

Biosimilars (EU) (rDNA amp hybridoma derived)

Off Patent Biologicals (All)

and so on

Definition is Market and Commerce based

527

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

bullMore than 325 million patients worldwide have been helped by biotech medicinesbullMore than 50 of medicines in development are biotech medicines

627

EU View Biosimilars are not generic pharmaceuticalsndashGenerics are clinically identical to their reference productsndashBiosimilars can never be identical to their reference products1048707Due to the complexity amp variability of a biological the quality profile is determined by the manufacturing processndashthe product is the process1048707Differences in process are inevitable between different manufacturersndashminor process differences can lead to marked differences in clinical profile

727

Biosimilars are similar not identical to original biotech products

Biosimilars are similarhelliphellip hellipNot Identical

Different cell lines Different mfg process

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

827

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

Safety and efficacy can differ significantly with small changes in ndashprotein biophysical characteristics or ndashformulation of the drug producLong 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

927

INDIAN Scenario

No Biosimilar only Biogeneric as in USA

No Guidelines

Schedule Y of Drugs and Cosmetics Act

EMEAICH Guidelines

More than 20 products approved so far

Guidelines to be put in place soon

1027

Biogeneric products approved so far in India

Sal No1234567

89

101112

MoleculeHuman insulin Erythropoietin Hepatitis B vaccine Human growth hormoneInterleukin 2Interleukin 11Granulocyte Colony Stimulating FactorColony Stimulating FactorInterferon2AlphaInterferon 2BetaInterferons GammaStreptokinase

Sal No13

1415

1617

18

19

20

MoleculeTissue PlasminogenActivatorBlood factor VIIIFollicle stimulating hormoneTeriparatide (Forteo)Drerecogin (Xigris) alphaPlatelet Derived Growth factor (PDGF)Epidermal Growth factor (EGF)Eptacogalpha (r-F VIIa) r-coagulation factor

Refer DBT Website wwwigmorisnicin

1127

The Primary Goals of Preclinical Safety Evaluation are

bull Identify an initial safe dose and subsequent

dose escalation schemes in humans

bull Identify potential target organs for toxicity and

for reversibility

bull Identify safety parameters for clinical

monitoring

1227

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

1327

The Test Substances

bullInvestigational new drug or new entities

bullBiologically similar to an already tested

and used drug or molecule as a biologic

bull What to term it Biogeneric Biosimilar

Or

1427

Comparability

Evaluated on the basis of biochemical and

biological characterization (ie identity

purity stability and potency)

In some cases additional studies may be

needed (ie pharmacokinetics pharmaco-

dynamics and or safety)

1527

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

1627

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

1727

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

1827

Species to be Studied Safety evaluation programs should normally include two

relevant species

one relevant species may suffice (eg 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 (eg if the toxicity profile in the two species is comparable in the short term)

1927

When No RelevantSpecies 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 eg a repeated dose toxicity study of lt 14 days duration that includes an evaluation of important functional endpoints (eg cardiovascular and respiratory)

2027

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

sizephysiology of the animal species

Two routes otherwise is not required

2127

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

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

427

Worldwide off Patent Biotech Medicines often referred as

Generic Biophamaceuticals (USA)

Biogenerics (USA)

Follow-on Biologics (USA)

Biosimilars (EU) (rDNA amp hybridoma derived)

Off Patent Biologicals (All)

and so on

Definition is Market and Commerce based

527

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

bullMore than 325 million patients worldwide have been helped by biotech medicinesbullMore than 50 of medicines in development are biotech medicines

627

EU View Biosimilars are not generic pharmaceuticalsndashGenerics are clinically identical to their reference productsndashBiosimilars can never be identical to their reference products1048707Due to the complexity amp variability of a biological the quality profile is determined by the manufacturing processndashthe product is the process1048707Differences in process are inevitable between different manufacturersndashminor process differences can lead to marked differences in clinical profile

727

Biosimilars are similar not identical to original biotech products

Biosimilars are similarhelliphellip hellipNot Identical

Different cell lines Different mfg process

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

827

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

Safety and efficacy can differ significantly with small changes in ndashprotein biophysical characteristics or ndashformulation of the drug producLong 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

927

INDIAN Scenario

No Biosimilar only Biogeneric as in USA

No Guidelines

Schedule Y of Drugs and Cosmetics Act

EMEAICH Guidelines

More than 20 products approved so far

Guidelines to be put in place soon

1027

Biogeneric products approved so far in India

Sal No1234567

89

101112

MoleculeHuman insulin Erythropoietin Hepatitis B vaccine Human growth hormoneInterleukin 2Interleukin 11Granulocyte Colony Stimulating FactorColony Stimulating FactorInterferon2AlphaInterferon 2BetaInterferons GammaStreptokinase

Sal No13

1415

1617

18

19

20

MoleculeTissue PlasminogenActivatorBlood factor VIIIFollicle stimulating hormoneTeriparatide (Forteo)Drerecogin (Xigris) alphaPlatelet Derived Growth factor (PDGF)Epidermal Growth factor (EGF)Eptacogalpha (r-F VIIa) r-coagulation factor

Refer DBT Website wwwigmorisnicin

1127

The Primary Goals of Preclinical Safety Evaluation are

bull Identify an initial safe dose and subsequent

dose escalation schemes in humans

bull Identify potential target organs for toxicity and

for reversibility

bull Identify safety parameters for clinical

monitoring

1227

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

1327

The Test Substances

bullInvestigational new drug or new entities

bullBiologically similar to an already tested

and used drug or molecule as a biologic

bull What to term it Biogeneric Biosimilar

Or

1427

Comparability

Evaluated on the basis of biochemical and

biological characterization (ie identity

purity stability and potency)

In some cases additional studies may be

needed (ie pharmacokinetics pharmaco-

dynamics and or safety)

1527

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

1627

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

1727

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

1827

Species to be Studied Safety evaluation programs should normally include two

relevant species

one relevant species may suffice (eg 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 (eg if the toxicity profile in the two species is comparable in the short term)

1927

When No RelevantSpecies 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 eg a repeated dose toxicity study of lt 14 days duration that includes an evaluation of important functional endpoints (eg cardiovascular and respiratory)

2027

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

sizephysiology of the animal species

Two routes otherwise is not required

2127

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

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

527

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

bullMore than 325 million patients worldwide have been helped by biotech medicinesbullMore than 50 of medicines in development are biotech medicines

627

EU View Biosimilars are not generic pharmaceuticalsndashGenerics are clinically identical to their reference productsndashBiosimilars can never be identical to their reference products1048707Due to the complexity amp variability of a biological the quality profile is determined by the manufacturing processndashthe product is the process1048707Differences in process are inevitable between different manufacturersndashminor process differences can lead to marked differences in clinical profile

727

Biosimilars are similar not identical to original biotech products

Biosimilars are similarhelliphellip hellipNot Identical

Different cell lines Different mfg process

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

827

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

Safety and efficacy can differ significantly with small changes in ndashprotein biophysical characteristics or ndashformulation of the drug producLong 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

927

INDIAN Scenario

No Biosimilar only Biogeneric as in USA

No Guidelines

Schedule Y of Drugs and Cosmetics Act

EMEAICH Guidelines

More than 20 products approved so far

Guidelines to be put in place soon

1027

Biogeneric products approved so far in India

Sal No1234567

89

101112

MoleculeHuman insulin Erythropoietin Hepatitis B vaccine Human growth hormoneInterleukin 2Interleukin 11Granulocyte Colony Stimulating FactorColony Stimulating FactorInterferon2AlphaInterferon 2BetaInterferons GammaStreptokinase

Sal No13

1415

1617

18

19

20

MoleculeTissue PlasminogenActivatorBlood factor VIIIFollicle stimulating hormoneTeriparatide (Forteo)Drerecogin (Xigris) alphaPlatelet Derived Growth factor (PDGF)Epidermal Growth factor (EGF)Eptacogalpha (r-F VIIa) r-coagulation factor

Refer DBT Website wwwigmorisnicin

1127

The Primary Goals of Preclinical Safety Evaluation are

bull Identify an initial safe dose and subsequent

dose escalation schemes in humans

bull Identify potential target organs for toxicity and

for reversibility

bull Identify safety parameters for clinical

monitoring

1227

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

1327

The Test Substances

bullInvestigational new drug or new entities

bullBiologically similar to an already tested

and used drug or molecule as a biologic

bull What to term it Biogeneric Biosimilar

Or

1427

Comparability

Evaluated on the basis of biochemical and

biological characterization (ie identity

purity stability and potency)

In some cases additional studies may be

needed (ie pharmacokinetics pharmaco-

dynamics and or safety)

1527

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

1627

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

1727

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

1827

Species to be Studied Safety evaluation programs should normally include two

relevant species

one relevant species may suffice (eg 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 (eg if the toxicity profile in the two species is comparable in the short term)

1927

When No RelevantSpecies 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 eg a repeated dose toxicity study of lt 14 days duration that includes an evaluation of important functional endpoints (eg cardiovascular and respiratory)

2027

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

sizephysiology of the animal species

Two routes otherwise is not required

2127

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

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

627

EU View Biosimilars are not generic pharmaceuticalsndashGenerics are clinically identical to their reference productsndashBiosimilars can never be identical to their reference products1048707Due to the complexity amp variability of a biological the quality profile is determined by the manufacturing processndashthe product is the process1048707Differences in process are inevitable between different manufacturersndashminor process differences can lead to marked differences in clinical profile

727

Biosimilars are similar not identical to original biotech products

Biosimilars are similarhelliphellip hellipNot Identical

Different cell lines Different mfg process

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

827

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

Safety and efficacy can differ significantly with small changes in ndashprotein biophysical characteristics or ndashformulation of the drug producLong 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

927

INDIAN Scenario

No Biosimilar only Biogeneric as in USA

No Guidelines

Schedule Y of Drugs and Cosmetics Act

EMEAICH Guidelines

More than 20 products approved so far

Guidelines to be put in place soon

1027

Biogeneric products approved so far in India

Sal No1234567

89

101112

MoleculeHuman insulin Erythropoietin Hepatitis B vaccine Human growth hormoneInterleukin 2Interleukin 11Granulocyte Colony Stimulating FactorColony Stimulating FactorInterferon2AlphaInterferon 2BetaInterferons GammaStreptokinase

Sal No13

1415

1617

18

19

20

MoleculeTissue PlasminogenActivatorBlood factor VIIIFollicle stimulating hormoneTeriparatide (Forteo)Drerecogin (Xigris) alphaPlatelet Derived Growth factor (PDGF)Epidermal Growth factor (EGF)Eptacogalpha (r-F VIIa) r-coagulation factor

Refer DBT Website wwwigmorisnicin

1127

The Primary Goals of Preclinical Safety Evaluation are

bull Identify an initial safe dose and subsequent

dose escalation schemes in humans

bull Identify potential target organs for toxicity and

for reversibility

bull Identify safety parameters for clinical

monitoring

1227

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

1327

The Test Substances

bullInvestigational new drug or new entities

bullBiologically similar to an already tested

and used drug or molecule as a biologic

bull What to term it Biogeneric Biosimilar

Or

1427

Comparability

Evaluated on the basis of biochemical and

biological characterization (ie identity

purity stability and potency)

In some cases additional studies may be

needed (ie pharmacokinetics pharmaco-

dynamics and or safety)

1527

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

1627

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

1727

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

1827

Species to be Studied Safety evaluation programs should normally include two

relevant species

one relevant species may suffice (eg 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 (eg if the toxicity profile in the two species is comparable in the short term)

1927

When No RelevantSpecies 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 eg a repeated dose toxicity study of lt 14 days duration that includes an evaluation of important functional endpoints (eg cardiovascular and respiratory)

2027

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

sizephysiology of the animal species

Two routes otherwise is not required

2127

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

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

727

Biosimilars are similar not identical to original biotech products

Biosimilars are similarhelliphellip hellipNot Identical

Different cell lines Different mfg process

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

827

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

Safety and efficacy can differ significantly with small changes in ndashprotein biophysical characteristics or ndashformulation of the drug producLong 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

927

INDIAN Scenario

No Biosimilar only Biogeneric as in USA

No Guidelines

Schedule Y of Drugs and Cosmetics Act

EMEAICH Guidelines

More than 20 products approved so far

Guidelines to be put in place soon

1027

Biogeneric products approved so far in India

Sal No1234567

89

101112

MoleculeHuman insulin Erythropoietin Hepatitis B vaccine Human growth hormoneInterleukin 2Interleukin 11Granulocyte Colony Stimulating FactorColony Stimulating FactorInterferon2AlphaInterferon 2BetaInterferons GammaStreptokinase

Sal No13

1415

1617

18

19

20

MoleculeTissue PlasminogenActivatorBlood factor VIIIFollicle stimulating hormoneTeriparatide (Forteo)Drerecogin (Xigris) alphaPlatelet Derived Growth factor (PDGF)Epidermal Growth factor (EGF)Eptacogalpha (r-F VIIa) r-coagulation factor

Refer DBT Website wwwigmorisnicin

1127

The Primary Goals of Preclinical Safety Evaluation are

bull Identify an initial safe dose and subsequent

dose escalation schemes in humans

bull Identify potential target organs for toxicity and

for reversibility

bull Identify safety parameters for clinical

monitoring

1227

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

1327

The Test Substances

bullInvestigational new drug or new entities

bullBiologically similar to an already tested

and used drug or molecule as a biologic

bull What to term it Biogeneric Biosimilar

Or

1427

Comparability

Evaluated on the basis of biochemical and

biological characterization (ie identity

purity stability and potency)

In some cases additional studies may be

needed (ie pharmacokinetics pharmaco-

dynamics and or safety)

1527

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

1627

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

1727

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

1827

Species to be Studied Safety evaluation programs should normally include two

relevant species

one relevant species may suffice (eg 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 (eg if the toxicity profile in the two species is comparable in the short term)

1927

When No RelevantSpecies 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 eg a repeated dose toxicity study of lt 14 days duration that includes an evaluation of important functional endpoints (eg cardiovascular and respiratory)

2027

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

sizephysiology of the animal species

Two routes otherwise is not required

2127

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

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

827

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

Safety and efficacy can differ significantly with small changes in ndashprotein biophysical characteristics or ndashformulation of the drug producLong 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

927

INDIAN Scenario

No Biosimilar only Biogeneric as in USA

No Guidelines

Schedule Y of Drugs and Cosmetics Act

EMEAICH Guidelines

More than 20 products approved so far

Guidelines to be put in place soon

1027

Biogeneric products approved so far in India

Sal No1234567

89

101112

MoleculeHuman insulin Erythropoietin Hepatitis B vaccine Human growth hormoneInterleukin 2Interleukin 11Granulocyte Colony Stimulating FactorColony Stimulating FactorInterferon2AlphaInterferon 2BetaInterferons GammaStreptokinase

Sal No13

1415

1617

18

19

20

MoleculeTissue PlasminogenActivatorBlood factor VIIIFollicle stimulating hormoneTeriparatide (Forteo)Drerecogin (Xigris) alphaPlatelet Derived Growth factor (PDGF)Epidermal Growth factor (EGF)Eptacogalpha (r-F VIIa) r-coagulation factor

Refer DBT Website wwwigmorisnicin

1127

The Primary Goals of Preclinical Safety Evaluation are

bull Identify an initial safe dose and subsequent

dose escalation schemes in humans

bull Identify potential target organs for toxicity and

for reversibility

bull Identify safety parameters for clinical

monitoring

1227

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

1327

The Test Substances

bullInvestigational new drug or new entities

bullBiologically similar to an already tested

and used drug or molecule as a biologic

bull What to term it Biogeneric Biosimilar

Or

1427

Comparability

Evaluated on the basis of biochemical and

biological characterization (ie identity

purity stability and potency)

In some cases additional studies may be

needed (ie pharmacokinetics pharmaco-

dynamics and or safety)

1527

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

1627

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

1727

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

1827

Species to be Studied Safety evaluation programs should normally include two

relevant species

one relevant species may suffice (eg 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 (eg if the toxicity profile in the two species is comparable in the short term)

1927

When No RelevantSpecies 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 eg a repeated dose toxicity study of lt 14 days duration that includes an evaluation of important functional endpoints (eg cardiovascular and respiratory)

2027

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

sizephysiology of the animal species

Two routes otherwise is not required

2127

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

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

927

INDIAN Scenario

No Biosimilar only Biogeneric as in USA

No Guidelines

Schedule Y of Drugs and Cosmetics Act

EMEAICH Guidelines

More than 20 products approved so far

Guidelines to be put in place soon

1027

Biogeneric products approved so far in India

Sal No1234567

89

101112

MoleculeHuman insulin Erythropoietin Hepatitis B vaccine Human growth hormoneInterleukin 2Interleukin 11Granulocyte Colony Stimulating FactorColony Stimulating FactorInterferon2AlphaInterferon 2BetaInterferons GammaStreptokinase

Sal No13

1415

1617

18

19

20

MoleculeTissue PlasminogenActivatorBlood factor VIIIFollicle stimulating hormoneTeriparatide (Forteo)Drerecogin (Xigris) alphaPlatelet Derived Growth factor (PDGF)Epidermal Growth factor (EGF)Eptacogalpha (r-F VIIa) r-coagulation factor

Refer DBT Website wwwigmorisnicin

1127

The Primary Goals of Preclinical Safety Evaluation are

bull Identify an initial safe dose and subsequent

dose escalation schemes in humans

bull Identify potential target organs for toxicity and

for reversibility

bull Identify safety parameters for clinical

monitoring

1227

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

1327

The Test Substances

bullInvestigational new drug or new entities

bullBiologically similar to an already tested

and used drug or molecule as a biologic

bull What to term it Biogeneric Biosimilar

Or

1427

Comparability

Evaluated on the basis of biochemical and

biological characterization (ie identity

purity stability and potency)

In some cases additional studies may be

needed (ie pharmacokinetics pharmaco-

dynamics and or safety)

1527

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

1627

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

1727

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

1827

Species to be Studied Safety evaluation programs should normally include two

relevant species

one relevant species may suffice (eg 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 (eg if the toxicity profile in the two species is comparable in the short term)

1927

When No RelevantSpecies 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 eg a repeated dose toxicity study of lt 14 days duration that includes an evaluation of important functional endpoints (eg cardiovascular and respiratory)

2027

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

sizephysiology of the animal species

Two routes otherwise is not required

2127

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

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

1027

Biogeneric products approved so far in India

Sal No1234567

89

101112

MoleculeHuman insulin Erythropoietin Hepatitis B vaccine Human growth hormoneInterleukin 2Interleukin 11Granulocyte Colony Stimulating FactorColony Stimulating FactorInterferon2AlphaInterferon 2BetaInterferons GammaStreptokinase

Sal No13

1415

1617

18

19

20

MoleculeTissue PlasminogenActivatorBlood factor VIIIFollicle stimulating hormoneTeriparatide (Forteo)Drerecogin (Xigris) alphaPlatelet Derived Growth factor (PDGF)Epidermal Growth factor (EGF)Eptacogalpha (r-F VIIa) r-coagulation factor

Refer DBT Website wwwigmorisnicin

1127

The Primary Goals of Preclinical Safety Evaluation are

bull Identify an initial safe dose and subsequent

dose escalation schemes in humans

bull Identify potential target organs for toxicity and

for reversibility

bull Identify safety parameters for clinical

monitoring

1227

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

1327

The Test Substances

bullInvestigational new drug or new entities

bullBiologically similar to an already tested

and used drug or molecule as a biologic

bull What to term it Biogeneric Biosimilar

Or

1427

Comparability

Evaluated on the basis of biochemical and

biological characterization (ie identity

purity stability and potency)

In some cases additional studies may be

needed (ie pharmacokinetics pharmaco-

dynamics and or safety)

1527

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

1627

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

1727

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

1827

Species to be Studied Safety evaluation programs should normally include two

relevant species

one relevant species may suffice (eg 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 (eg if the toxicity profile in the two species is comparable in the short term)

1927

When No RelevantSpecies 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 eg a repeated dose toxicity study of lt 14 days duration that includes an evaluation of important functional endpoints (eg cardiovascular and respiratory)

2027

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

sizephysiology of the animal species

Two routes otherwise is not required

2127

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

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

1127

The Primary Goals of Preclinical Safety Evaluation are

bull Identify an initial safe dose and subsequent

dose escalation schemes in humans

bull Identify potential target organs for toxicity and

for reversibility

bull Identify safety parameters for clinical

monitoring

1227

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

1327

The Test Substances

bullInvestigational new drug or new entities

bullBiologically similar to an already tested

and used drug or molecule as a biologic

bull What to term it Biogeneric Biosimilar

Or

1427

Comparability

Evaluated on the basis of biochemical and

biological characterization (ie identity

purity stability and potency)

In some cases additional studies may be

needed (ie pharmacokinetics pharmaco-

dynamics and or safety)

1527

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

1627

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

1727

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

1827

Species to be Studied Safety evaluation programs should normally include two

relevant species

one relevant species may suffice (eg 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 (eg if the toxicity profile in the two species is comparable in the short term)

1927

When No RelevantSpecies 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 eg a repeated dose toxicity study of lt 14 days duration that includes an evaluation of important functional endpoints (eg cardiovascular and respiratory)

2027

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

sizephysiology of the animal species

Two routes otherwise is not required

2127

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

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

1227

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

1327

The Test Substances

bullInvestigational new drug or new entities

bullBiologically similar to an already tested

and used drug or molecule as a biologic

bull What to term it Biogeneric Biosimilar

Or

1427

Comparability

Evaluated on the basis of biochemical and

biological characterization (ie identity

purity stability and potency)

In some cases additional studies may be

needed (ie pharmacokinetics pharmaco-

dynamics and or safety)

1527

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

1627

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

1727

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

1827

Species to be Studied Safety evaluation programs should normally include two

relevant species

one relevant species may suffice (eg 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 (eg if the toxicity profile in the two species is comparable in the short term)

1927

When No RelevantSpecies 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 eg a repeated dose toxicity study of lt 14 days duration that includes an evaluation of important functional endpoints (eg cardiovascular and respiratory)

2027

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

sizephysiology of the animal species

Two routes otherwise is not required

2127

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

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

1327

The Test Substances

bullInvestigational new drug or new entities

bullBiologically similar to an already tested

and used drug or molecule as a biologic

bull What to term it Biogeneric Biosimilar

Or

1427

Comparability

Evaluated on the basis of biochemical and

biological characterization (ie identity

purity stability and potency)

In some cases additional studies may be

needed (ie pharmacokinetics pharmaco-

dynamics and or safety)

1527

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

1627

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

1727

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

1827

Species to be Studied Safety evaluation programs should normally include two

relevant species

one relevant species may suffice (eg 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 (eg if the toxicity profile in the two species is comparable in the short term)

1927

When No RelevantSpecies 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 eg a repeated dose toxicity study of lt 14 days duration that includes an evaluation of important functional endpoints (eg cardiovascular and respiratory)

2027

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

sizephysiology of the animal species

Two routes otherwise is not required

2127

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

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

1427

Comparability

Evaluated on the basis of biochemical and

biological characterization (ie identity

purity stability and potency)

In some cases additional studies may be

needed (ie pharmacokinetics pharmaco-

dynamics and or safety)

1527

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

1627

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

1727

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

1827

Species to be Studied Safety evaluation programs should normally include two

relevant species

one relevant species may suffice (eg 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 (eg if the toxicity profile in the two species is comparable in the short term)

1927

When No RelevantSpecies 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 eg a repeated dose toxicity study of lt 14 days duration that includes an evaluation of important functional endpoints (eg cardiovascular and respiratory)

2027

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

sizephysiology of the animal species

Two routes otherwise is not required

2127

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

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

1527

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

1627

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

1727

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

1827

Species to be Studied Safety evaluation programs should normally include two

relevant species

one relevant species may suffice (eg 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 (eg if the toxicity profile in the two species is comparable in the short term)

1927

When No RelevantSpecies 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 eg a repeated dose toxicity study of lt 14 days duration that includes an evaluation of important functional endpoints (eg cardiovascular and respiratory)

2027

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

sizephysiology of the animal species

Two routes otherwise is not required

2127

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

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

1627

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

1727

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

1827

Species to be Studied Safety evaluation programs should normally include two

relevant species

one relevant species may suffice (eg 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 (eg if the toxicity profile in the two species is comparable in the short term)

1927

When No RelevantSpecies 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 eg a repeated dose toxicity study of lt 14 days duration that includes an evaluation of important functional endpoints (eg cardiovascular and respiratory)

2027

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

sizephysiology of the animal species

Two routes otherwise is not required

2127

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

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

1727

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

1827

Species to be Studied Safety evaluation programs should normally include two

relevant species

one relevant species may suffice (eg 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 (eg if the toxicity profile in the two species is comparable in the short term)

1927

When No RelevantSpecies 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 eg a repeated dose toxicity study of lt 14 days duration that includes an evaluation of important functional endpoints (eg cardiovascular and respiratory)

2027

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

sizephysiology of the animal species

Two routes otherwise is not required

2127

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

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

1827

Species to be Studied Safety evaluation programs should normally include two

relevant species

one relevant species may suffice (eg 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 (eg if the toxicity profile in the two species is comparable in the short term)

1927

When No RelevantSpecies 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 eg a repeated dose toxicity study of lt 14 days duration that includes an evaluation of important functional endpoints (eg cardiovascular and respiratory)

2027

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

sizephysiology of the animal species

Two routes otherwise is not required

2127

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

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

1927

When No RelevantSpecies 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 eg a repeated dose toxicity study of lt 14 days duration that includes an evaluation of important functional endpoints (eg cardiovascular and respiratory)

2027

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

sizephysiology of the animal species

Two routes otherwise is not required

2127

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

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

2027

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

sizephysiology of the animal species

Two routes otherwise is not required

2127

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

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

2127

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

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

2227

bull Immunogenicity

bull Antibody Formation In Humans

bull Safety Pharmacology

bull Pharmacokinetic studies

bull Single Dose Toxicity Studies

bull Repeated Dose Toxicity Studies

bull Immunotoxicity Studies

bull Reproductive Performance and Developmental Toxicity Studies

bull Genotoxicity Studies

bull Carcinogenicity Studies

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

2327

Carcinogenicity Studies 2

With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (eg 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

2427

2427