Biosimilars Scientific and Regulatory Considerations · 2018-04-02 · appropriate analytical...

Amgen Corporate Template 1

Biosimilars—Scientific and

Regulatory Considerations

Gustavo Grampp

Regulatory Policy Director, Amgen

Presented at Maryland Pharmacists Association meeting January 31, 2016

2

Program objectives

1. Review complexities of biologics and differences from chemical drugs

2. Introduce the US biosimilar regulatory framework

3. Learn about biosimilar development including design, analytical studies, and clinical studies

4. Discuss post-approval considerations including pharmacovigilance, interchangeability, and substitution

Grampp, Biosimilars—Scientific and Regulatory Considerations.

MPhA Meeting January 31, 2016

3

INTRODUCTION TO

BIOLOGICS

4

What is a biologic?

• Biologics are large protein-based therapeutics

– Biologics can include antibodies, recombinant proteins, or

fusion proteins

Monoclonal antibody

Neiderwieser D et al. Eur J Haematol 2011;86:277-288.




5

What is a biologic?

• Biologics are more complex in structure and function

than chemical drugs

Monoclonal antibody1

~150 kDa

1. Lipman NS et al. ILAR J. 2005;46:258-268. 2. Aspirin prescribing information. Available at:

http://www.fda.gov/ohrms/dockets/ac/03/briefing/4012B1_03_Appd%201-Professional%20Labeling.pdf. Accessed September 2015.

Up to 1000×

larger1,2

Acetylsalicylic acid2

~0.18 kDa



What is a biologic?

• Biologics are more complex in structure and function

than chemical drugs

Acetylsalicylic acidMonoclonal antibody

1. Roger SD. Nephrology 2006;11:341-346. 2. Prugnaud JL. Br J Clin Pharmacol 2007;65:619-620. 3. Genazzani AA et al. Biodrugs 2007;21:351-356.

Simple,2

well-defined3

Complex,

with post-translational

modifications1



7

Patient

treatment2

Formulation,1 fill,2

and finish2

Characterization

and stability2

Transfection of

DNA into host cell1

Isolation2 and purification1

Cell culture

and expansion1

Cell line

selection and development1

Refrigeration,2

storage,2 and transport1

Manufacturer establishes a

unique master cell bank1

Biologics are made by living cells

through well-controlled processes

1. Kresse GB. Eur J Pharm Biopharm. 2009;72:479-486. 2. Sharma BG. EJHP Practice. 2007;13:54-56.

A typical biotechnology manufacturing process includes multiple stages



So what is a biosimilar?

• According to the US FDA, a biosimilar is a biological

product that is highly similar to the reference product

• There are no clinically meaningful differences in terms

of:

– Safety

– Purity

– Potency

FDA, Food and Drug Administration.

US Food and Drug Administration. Available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm291128.pdf. Accessed

September 2015.

Differences between biosimilars and reference biologics

are expected, but must not be clinically meaningful

In other words:




9

Each biosimilar is unique because of

differences in manufacturing

Known DNA sequence Unique manufacturing Unique biosimilar

1. Roger SD. Nephrology (Carlton) 2006;11:341-346. 2. Mellstedt H et al. Ann Oncol 2008;19:411-419.



Biosimilars are fundamentally different

from generics

MW, molecular weight.

1. Aspirin comprehensive prescribing information. Available at: www.fda.gov/ohrms/dockets/ac/03/briefing/4012B1_03_Appd%201Professional%20Labeling.pdf.

Accessed January 2013. 2. Genazzani AA et al. Biodrugs 2007;21:351-356. 3. Lipman NS et al. ILAR J 2005;46:258-268. 4. Roger SD. Nephrology 2006;11:341-346.

5. Prugnaud JL. Br J Clin Pharmacol 2007;65:619-620. 6. Gottlieb S. Am J Health Syst Pharm 2008;65(Suppl 6):S2-S8.

Monoclonal

antibody

Large2

MW = ~150,000 Da3

Each manufactured in a

unique living cell line2

Similar but not identical

copy can be made2

Sensitive to storage

and handling

conditions2


Small2

MW = 180 Da1

Predictable chemical

process

Identical copy can be

made2

Relatively stable2


Lower potential2

Simple5 and

well defined2

Easy to fully

characterize6

Monoclonal

antibody

Higher potential2

Complex with many

options for post-

translational

modification4

Difficult to

characterize fully

owing to a mixture of

related molecules6

STRUCTURE

CHARACTERIZATIONS

IMMUNOGENICITY

SIZE

MANUFACTURING

STABILITY

Biosimilars Generics Biosimilars Generics



11

Summary

Biologics are large, complex medicines developed in living systems

Biosimilars are highly similar, but not identical to the innovator biologic

Biosimilars differ from generics in complexity, manufacturing and sensitivity



REGULATORY FRAMEWORKS


13

The US biosimilars pathway was signed

into law along with the Affordable Care Act

Food and Drug Administration. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf.

Accessed 24 January 2013.

Extensive structural and functional characterization

Sufficient to demonstrate that the product is “highly similar” to the reference product and safe, pure, and potent for one or more approved conditions of use

FDA has discretion to determine that certain studies not required

Consider need for animal data to assess toxicity

Clinical studies to compare clinical immunogenicity and PK/PD

Biosimilars

Establish same active ingredient, strength, dosage form, route of administration, and condition of

use

Demonstration of bioequivalence

Generics



14

In contrast to the regulatory framework for

generics…

Same active

ingredients,

dosage form,

administration

route & strength

Same rate &

extent of

absorbance &

availability at

site (80-125%)

Interchangeability

Rating

Steven Kozlowski, M.D. Director Office of Biotechnology Products/OPS/CDER. Available at http://www.biosimilarstoday.com/Kozlowski.pdf

PE = Pharmaceutical Equivalence

BE = Bioequivalence

TE = Therapeutic Equivalence “Same” Structure = “Same” Function

“Same (Identity)” = “Identical (Identity)”

Pharmaceutical

EquivalenceBioequivalence

Therapeutic

Equivalence



15

• The FDA will consider the totality of evidence

provided3

– Comparative assessment of the structure

and function

– Nonclinical evaluation

– Human PK/PD

– Clinical immunogenicity

– Clinical safety and efficacy, as needed

• The purpose of the biosimilar development

program is to demonstrate that the biosimilar is highly similar to the reference product and

not to independently establish its safety and

effectiveness3

• The type and extent of analyses and testing

that are needed to demonstrate biosimilarity

will be determined on a case-by-case basis3

1. Kozlowski S. Presented at: Biotechnology Technology Summit; June 13, 2014; Rockville, MD.

https://www.ibbr.umd.edu/sites/default/files/public_page/Kozlowski%20-%20Biomanufacturing%20Summit.pdf. Accessed February 5, 2015.

2. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2015.

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed April 30, 2015.


http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed February 7, 2015.

Clinical Pharm.(PK/PD)

Nonclinical

Analytical Characterization (Structure & Function

Assessment)

Safety, Efficacy, and

Immunogenicity

One study to inform

immunogenicity and will

likely need at least one

clinical study in a

sensitive population to

confirm safety

and efficacy2

Clinical

studies1

FDA recommends a “Totality of Evidence” and a

stepwise approach for biosimilar development

FDA, Food and Drug Administration; PD, pharmacodynamics; PK, pharmacokinetics.

16

1. Patient Protection and Affordable Care Act. 2009. http://www.gpo.gov/fdsys/pkg/BILLS-111hr3590pp/pdf/BILLS-111hr3590pp.pdf. Accessed April 30, 2015.

2. Camacho L, et al. Cancer Med. 2014;3:889-899.

• The United States is the only country with a specific definition for an interchangeable biologic2

• Studies needed to obtain the interchangeability designation are not yet determined by the FDA2

FDA, Food and Drug Administration.

Approved as a biosimilarApproved as an

interchangeable biologic

Additional evidence is needed to demonstrate interchangeability1

Can be expected to produce the same clinical result as the reference product in any given patient

AND

For a product that is administered more than once, there is no additional risk in terms of safety or diminished efficacy as a result of switchingbetween the biosimilar and the reference product compared with using

the reference product alone

Demonstration of biosimilarity is the first step -

interchangeability has additional requirements



http://www.biosimilarstoday.com/Kozlowski.pdf

https://www.ibbr.umd.edu/sites/default/files/public_page/Kozlowski - Biomanufacturing Summit.pdf

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf


http://www.gpo.gov/fdsys/pkg/BILLS-111hr3590pp/pdf/BILLS-111hr3590pp.pdf


17

Summary

The US pathway for approval of biosimilars was signed into law along with the Patient Protection and Affordable Care Act

A totality of evidence will be considered when evaluating a biosimilar product for approval

Determination of interchangeability requires additional evidence



DEVELOPMENT OF

BIOSIMILARS



19

Biosimilar manufacturers start with no

knowledge of the reference product

• Purchase and analyze reference product

• Determine amino acid sequence

• Characterize product, including glycosylation

• Understand structure–function

• Determine critical quality attributes

?

Kozlowski S. Presented at: Biotechnology Technology Summit; June 13, 2014; Rockville, MD. Available at:

https://www.ibbr.umd.edu/sites/default/files/public_page/Kozlowski%20-%20Biomanufacturing%20Summit.pdf. Accessed February 2015.



Biosimilar development requires reverse engineering,

starting with reference product characterization

Stability

Primary structure

Biological function

Receptor binding and

immuno-chemical properties

Process-related

impurities

General properties

and excipients

Higher order

structureProduct-related

substances and

impurities

Attributes related to the amino acid

sequence and all post-translational modifications, including glycans

Biological and functional

activities, including receptor binding and immunochemical properties

Degradation

profiles denoting stability

Quantitative levels of

product variants and their identities

Kinetics and thermodynamics

of binding, related to functional activity

Integrity of the secondary,

tertiary, and quaternary structure

Properties of the finished

drug product, including strength and formulation

Impurities from host cells

and downstream process

US Food and Drug Administration. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291134.pdf. Accessed

September 2015.




21

Biosimilar manufacturers create a unique cell

line and a unique manufacturing process

Known1 AnalyticsUnknown2

DNAsequence

Cell line

Growth media

Method of cell expansion

Bioreactor conditions

Protein recovery conditions

Purification conditions

Formulation methods

Reagents

Reference standards

Compare structure and

function

To reverse engineer a reference product, each

biosimilar developer must create a manufacturing

process for that biologic de novo2

1. Mellstedt H et al. Ann Oncol 2008;19:411-419. 2. Roger SD. Nephrology (Carlton) 2006;11:341-346.



Biosimilar

1. Quality

Cross reference

2. Non-Clinical

3. Clinical

Cross reference

Cross reference –Prior findings of safety and

efficacy

Integrated Biosimilarity Exercise –Quality, Safety and Efficacy

Originator BLA

A stepwise development program follows

after reverse engineering

Food and Drug Administration. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf.

Accessed 24 January 2013.

Clinical studies

Nonclinical


Assessment)

Biosimilar?

Biosimilar?

Biosimilar?



23

Stepwise assessment begins with extensive

structural and functional comparisons

FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012.



Assessment)

• Foundational for biosimilar

development program

• Involves structural and functional

characterization of reference

product

• Involves the determination of

differences in relevant critical

attributes between biosimilar and

reference product using

appropriate analytical

methodology



Comparisons assess alignment of many

attributes, with emphasis on critical attribute

Primary structure2

High-order structure2

Biological2

Product-related substances and impurities2

Process-related impurities2

Product degradation2

1. Adapted from Foraker S. http://investors.amgen.com/phoenix.zhtml?c=61656&p=irol-presentations. Accessed March 5, 2015. 2. FDA. Guidance for Industry: Quality

Considerations in Demonstrating Biosimilarity to a Reference Protein Product. 2012.


Adapted from Foraker S, provided October 28, 2014, as part of an oral presentation and is qualified by such, containing forward-looking statements, and actual

results may vary materially; Amgen disclaims any duty to update.

ABP, Amgen biosimilar product; EU, European Union; US, United States.

Sample exercise: Biosimilar attributes

compared with reference product1

Biosimilar

vs US

reference

product

Biosimilar

vs EU

reference

product

Attributes

matched91 93

Attributes not

matched, but

not critical

4 2

Attributes not

matched and

critical

0 0

General properties1

Particles and aggregates1




http://investors.amgen.com/phoenix.zhtml?c=61656&p=irol-presentations



25

Toxicity assessments based on data

from animal studies are useful



• Animal toxicity data are useful when

uncertainties remain about safety of

biosimilar after extensive structural

and functional characterization

• Not warranted if biosimilar has been

demonstrated to be highly similar to

reference through analytical

characterization

Nonclinical




Clinical pharmacology studies are a

critical part of demonstrating biosimilarity


http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed February 7, 2015. 2. FDA. Guidance for Industry: Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product. 2014. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM397017.pdf. 3. Park W, et al. Ann Rheum Dis.

2013;72:1605-1612.

• Comparative human PK and PD studies are fundamental

components in demonstrating there no clinically meaningful

differences between reference and biosimilar1

• PK studies should demonstrate similar exposure over time and

PD studies should demonstrate similar effect on clinically

relevant PD measure(s) related to efficacy or safety concerns1

• Important PK parameters that are commonly studied include

AUC and Cmax2

Biosimilar

Reference

Example of PK of biosimilar that is highly

similar to that of the reference3

Mean

(±S

D)

seru

m

co

ncen

trati

on

, µ

g/m

L

AUC, area under the concentration-time curve; Cmax, maximum concentration; PD, pharmacodynamics; PK, pharmacokinetics; SD, standard deviation. aBiosimilar N=113.

Figure reproduced from Park W, et al. Ann Rheum Dis. 2013;72:1605-1612. With permission from BMJ Publishing Group Ltd.

27

Immunogenicity studies are critical for

establishing biosimilarity





• The goal of immunogenicity studies is

to establish that there are no clinically

meaningful differences in incidence and

severity of human immune response

between the biosimilar and reference

product2

Safety, Efficacy, and

Immunogenicity

One clinical study in

a sensitive population

to inform

immunogenicity1

Clinical

Studies

• Immunogenicity can be tested during

clinical safety and efficacy studies,

including PK/PD studies1

• Studies should be conducted in sensitive

population2

• Studies should include assessment of

binding and neutralizing antibodies2

PD, pharmacodynamics; PK, pharmacokinetics.

Clinical Pharm. PK/PD

28

Comparative clinical safety and efficacy

assessments may address residual uncertainties


Nonclinical


Assessment)

Clinical Studies

(Safety,

Efficacy)1

1. Kozlowski S. Presented at: Biotechnology Technology Summit; June 13, 2014; Rockville, MD.

https://www.ibbr.umd.edu/sites/default/files/public_page/Kozlowski%20-%20Biomanufacturing%20Summit.pdf. Accessed February 5, 2015.



Factors that affect the type and extent of clinical efficacy and safety

studies needed2

• Nature and complexity of the reference

• Mechanism of action of reference and disease pathology

• Extent of clinical experience with the reference and its therapeutic class

• Extent to which differences in structure and function studies predict differences in clinical outcomes

• Extent to which PK and PD studies predict clinical outcomes (eg, are sensitive PD markers available)

PD, pharmacodynamics; PK, pharmacokinetics.






https://www.ibbr.umd.edu/sites/default/files/public_page/Kozlowski - Biomanufacturing Summit.pdf



29

Clinical confirmation: safety and efficacy



• The goal is to demonstrate that the biosimilar has neither

decreased nor increased activity compared with the

reference product and has similar immunogenicity

Clinical

Studies

(Safety,

Efficacy)

Study design • Two-sided test to demonstrate equivalence; with an appropriate equivalence

margin

– A one-sided noninferiority design more appropriate in certain

circumstances

Endpoints and

study population

• Clinically relevant and sensitive in detecting clinically meaningful differences

• Selected by considering comorbidities and effect on disease state (eg,

immunosuppressed)

Important

considerations

• Clinical trial should allow

– Sufficient exposure

– Detection of relevant safety signals

– Detection of clinically meaningful differences in effectiveness and safety



Indication extrapolation is important to

biosimilar development

• A proposed biosimilar product may be licensed in one or

more additional conditions of use for which the reference

product is licensed, without additional clinical trials, if

appropriate scientific justification is provided

• Extrapolation is not automatic

AS, ankylosing spondylitis; CD, Crohn’s disease; PsA, psoriatic arthritis; PsO, psoriasis; RA, rheumatoid arthritis; UC, ulcerative colitis.

US Food and Drug Administration. Available at:

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm291128.pdf. Accessed September 2015.

Reference product studies

RA

PsA

Biosimilar studies

Extrapolated indications

RA PsO+

+

+

AS CD+

AS

PsO CD

UC

+

+

PsA + UC+

+

31

FDA recommendations address

considerations related to extrapolation

1. Dörner T, et al. Ann Rheum Dis. 2013;72:322-328. 2. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product.

2012. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed February 7, 2015.

Potential for distinct MOA in each

therapeutic indication

Variable optimal doses for efficacy

or safety profiles in different

patient groups

Influence of individual patient

characteristics on treatment

response

• Extrapolation is considered on case-by-case basis

• When MOA is not fully understood, separate

clinical trials in each indication are likely

necessary

• Biological data covering all functional aspects of agent, demonstrating high similarity to reference,

is required

• Data are produced using patient population and

clinical endpoint most sensitive to detect clinically

meaningful differences in efficacy and safety

• Careful consideration must be given to

comorbidities/concomitant medications and

intersubject variability

Considerations1 FDA recommendations2

FDA, Food and Drug Administration; MOA, mechanism of action.



Summary:

Pillars of Biosimilar Development

Biosimilar development starts with reverse engineering of the reference product quality attributes

Physiochemical and functional characterization of both the reference and the biosimilar is foundational to stepwise development

Comparative human PK and PD studies demonstrating absence of clinically meaningful differences between reference and biosimilar are critical to establishing biosimilarity

Immunogenicity testing demonstrating no clinically meaningful differences in incidence and severity is required

It is likely that at least one clinical study in a sensitive population is needed to confirm safety and efficacy and inform immunogenicity

Appropriate scientific justification is required to allow extrapolation of indications of use for which the reference is licensed

FDA, Food and Drug Administration; PD, pharmacodynamics; PK, pharmacokinetics.






33

POST-APPROVAL CONSIDERATIONS

34

Ongoing pharmacovigilance is important

for biologics and biosimilars



Robust post-marketing safety monitoring is important to ensure similar safety and effectiveness between the biosimilar and the reference drug

Safety monitoring should take into account the safety or effectiveness concerns associated with reference product

Safety monitoring should have the ability to differentiate between adverse events associated with the proposed biosimilar product vs those associated with the reference drug or other biosimilars



35

Why the practitioner needs to know

what product a patient received

• Sensitivity and complexity

• Manufacturing changes

Variability

• Immune response

• Potential “drift” between products

Safety Monitoring

• Access to accurate and complete medication histories

Medical Records

Requires

Justifies

“[C]ompanies will make manufacturing-related

changes to biologics periodically … and even small changes could affect safety or efficacy.”

– FDA1

CVS for

Refill #1

WalgreensRefill #2

Independentpharmacy Refill #3

Doctors

Office

Patient Record

1. Kozlowski S et al. N Engl J Med. 2011;365:385-388.



Class effect vs. product specific effect

Source: Casadevall Nicole, Immune-response and adverse reactions: PRCA case example. Presentation to EMA Nov, 2009. Available at

http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2009/11/WC500011064.pdf

Proximal agent is not always the casual agent!


http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2009/11/WC500011064.pdf


37

Additional evidence is needed to demonstrate interchangeability1

Can be expected to produce the same clinical result as the reference product

in any given patient

AND

For a product that is administered more than once, there is no additional risk to

safety or efficacy as a result of switching between the biosimilar and

the reference product

Interchangeability will require additional

evidence beyond approval as a biosimilar

1. US Food and Drug Administration. Available at:

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM444661.pdf. Accessed September 2015.

Approved

biosimilar

Approved,

interchangeable

biosimilar

The US is the only country with a specific definition

of an interchangeable biologic



In the US, state regulations govern

automatic substitution

FDA approves a

biologic as

interchangeable

with the reference

product1

State pharmacy

practice laws allow

for substitution of

an interchangeable

biologic2

Automatic

substitution

of an

interchangeable

biologic is

allowed

1. US Food and Drug Administration.

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm2

41718.htm. Accessed February 2015. 2. NCSL. State Laws and Legislation Related to Biologic Medications and Substitution of Biosimilars. 2014.

http://www.ncsl.org/documents/health/Biologics_BiosimilarsNCSLReport_July_2014.pdf. Accessed April 4, 2015.



39

Summary

Ongoing safety monitoring is critical to ensuring patient safety.

FDA has proposed a system of distinguishable nonproprietary names to help facilitate accurate and timely adverse event reporting.

FDA determines interchangeability and states determine the terms of pharmacy substitution of biologics



THANKS!

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