BIOSIMILARSBiosimilarity Concept

opportunities and challengesRequirements and impact on patients

Amir FarrokhianPharm. D, Pharmacotherapist

13Aban Pharmacotherapy Clinic, Tehran Uni. Medical Sciences

Gabric webinarAug 2020

The Importance of Biosimilar

Biopharmaceuticals represent one of the fastest-growing segmentsof pharmaceutical industry.

By 2010 they represented nearly 50% of the market.

Patent of original product will finally expire.

Increase opportunity to healthcare services, decrease expenditures,increase Patient access with lower price

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Definitions

Biologicals, Biosimilars

Biosimilar Products, the importance?

Requirements

There Are Two Type of Drugs

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Biologicals(eg. Insulins)

Chemicals(eg. A.S.A)

Innovatives,

(Brands):Aspirin

Non-Innovatives,

(Generics):Dispirin

Innovatives, (Brands):Lantus

Non-Innovatives,

(Biosimilars): Abasaglar

PATENTPATENT

Source Materials

Minor differences in manufacturing processes may influence clinical safety and efficacy

Kuhlmann et al. Nephrol Dial Transplant 2006; 21(Suppl 5): v4–8.

Choosing the DNA sequence

Differencesin DNA sequence can resultin variations of the recombinant protein produced

Cloning

Differencesin the expression system can lead to variations in the level of recombinant protein expression and stability

Differencesin growth conditions can result in variations inthe recombinant protein andby-products

Cultivation

Differences in the cell line can leadto variations inpost-translational modification ofthe recombinant protein

Protein production

Differences inthe purification process can result in variations inthe final product e.g. increased aggregate formation

Purification

Differences in formulation may influence the final product

Formulation

Different Process = Different Outcome (Product)

What is Biosimilar?• Biosimilar: is a biological product that is highly similar to and has no

clinically meaningful differences from an existing reference product.These two standards are described further below:

• Highly Similar: purity, chemical identity, and bioactivity• no clinically meaningful differences: No safety and effectiveness

difference.– This is generally demonstrated through human pharmacokinetic (exposure)

and pharmacodynamic (response) studies, an assessment of clinicalimmunogenicity, and clinical studies.

• Biosimilar competition should improve patient access to safe andeffective biological medicines with proven quality.

WWW.FDA.gov.ir

US –FDA, EMEA

RBP BS NCB

Originator, biosimilar and NCB - definitions

EXTERNAL EVENTS EXTERNAL EVENTS EXTERNAL EVENTS

Definition Reference BiothrepeuticProduct:

First product for whichmarketing authorisationwas granted for a givenactive substance on thebasis of comprehensivedocumentation of itsquality, non-clinical andclinical efficacy and safety

Biosimilar:

Biotherapeutic product forwhich biosimilarity to RBPwas demonstrated,meeting all requirementsof established regulatoryguidelines.

(e.g. WHO, FDA, EMA etc.)

Non-comparable biologics:

Biotherapeutic productapproved prior to adoptionor w/out existence of ascience-based BS pathway.

For such productssufficient clinical trials maynot have been conductedto prove its similarity to theRBP, in which case theyshould not be regarded assimilar

1 2 3

14*In some cases, SoC may not exist

EMA. EMA/CHMP/BMWP/403543/2010. 30 May 2012 ; EMA. EMEA/CHMP/BMWP/42832/2005 Rev1.18 Dec 2014; EMA. EMEA/CHMP/225411/2006. 4 Aug 2016 [accessed Dec 2016].

RBP BS NCB

Originator, biosimilar and NCB – clinical trials

EXTERNAL EVENTS EXTERNAL EVENTS EXTERNAL EVENTSAny Sensitive and

homogeneousNot defined

Superiority vs. standard of care (SoC)

Comparative head-to-head vs. RBP, normally equivalence

No robust/high-quality clinical development programme as defined by WHO guidelines or no clinical trials

Clinical outcomes or accepted / established surrogates (e.g. OS and PFS)

Sensitive, clinically-validated pharmacodynamic (PD) markers possible instead of clinical outcomes

Not defined

Patient Population

Clinical

Design

Study

Endpoints

1 2 3

15*In some cases, SoC may not exist

EMA. EMA/CHMP/BMWP/403543/2010. 30 May 2012 ; EMA. EMEA/CHMP/BMWP/42832/2005 Rev1.18 Dec 2014; EMA. EMEA/CHMP/225411/2006. 4 Aug 2016 [accessed Dec 2016].

RBP BS NCB

Originator, biosimilar and NCB –impact on patients

EXTERNAL EVENTS EXTERNAL EVENTS EXTERNAL EVENTS

Acceptable benefit/risk Considering Similar safety to RBP, no new findings

Only as reported in trials

Acceptable benefit/risk Considering Similar immunogenicity profile to RBP

Only if investigated

Safety

Immunogenicity

1 2 3

The Importance of Similarity

Similarity must be established at each stage of comparison with the reference product.

Molecular analytical similarity

Different molecular characteristics could have potential clinical consequences in patients resulting in theapproval of medicines with unknown clinical consequences.

Clinical similarity

No scientific basis exists to support that safety and effectiveness of the reference product applies to thebiosimilar version. Likewise, head-to-head comparison showing non-inferiority would not apply for biosimilarsbecause there could exist different clinical profiles between the reference and biosimilars.

Biosilmilar manufacturers need to show Similarity with both Analytical Methods & clinical

studies to demonstrate that the biosimilar has the same outcomes of Quality, Safety, andEfficacy as the Reference Product.

Letter from Dr. Ryoko Krause on behalf of IFPMA to Dr. Ivana Knezevic of the WHO. July 17, 2008

Introduction

Biologics are complex and identical copies cannot be made

• Biosimilars (recombinant proteins) are not generics

Roger et al. J Clin Pharm Ther 2008; 33(5): 459–64.

Subtle differences vs. reference products could be expected.

Although Biosimilars are advertised as having similar efficacy and safety to the originalbiologic, that is not always the case

Manufacture is a complex, multi-step process: different manufacturing processes mayresult in different products.

Manufacturers of Biosimilars formulate their own protocols.

Current analytical tools do not have the sensitivity to detect all clinically relevantdifferences between products

BIOSIMILARS ARE NOT IDENTICAL TO THE ORIGINAL BIOTHERAPEUTIC

• The “Process is the product”:– small changes in any step may create a structurally different product

• The development of a biosimilar depends on– its active substance and the manufacturing process

• Although biosimilar mAbs target the same receptors as originators,they are produced from different cell lines and manufacturingprocesses. Key differences are in:– DIFFERENT CELL LINES– DIFFERENT MANUFACTURING PROCESS

• The clinical significance of these differences, if any, is to be assessed inanalytical and clinical studies prior to approval. 20

Bio better Concept

2 Important Aspects

Safety

Efficacy

Introduction

Immunogenicity is a potential safety issue for biosimilars

Immunogenicity of a product cannot be predicted

and needs long-term safety monitoring to be established

Product quality may influence immunogenicity

e.g. impurities, aggregates

Minor differences in the manufacturing

process may influence immunogenicity

All biologics are potentially immunogenic

Immunogenicity may have

significant clinical consequences

Kuhlmann et al. Nephrol Dial Transplant 2006; 21 (Suppl 5): v4–8; Schellekens. Nephrol Dial Transplant 2003; 18: 1257–9

FDA docket .FDA-2005-P-G367; FDA response to FDA docket FDA-2005-P-G367

What is immunogenicity?

Immunogenicity

is the tendency

of a biologic to

induce an

unwanted

immune response

or to induce

immunologically

related adverse

events.

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The consequences of animmune reaction to atherapeutic protein may triggerfor many of the immunereactions and adverse eventsassociated with biologics.

All protein-based biologics have animmunogenic potential, i.e.activate immune response, inwhich B cells start generatingantibodies to this protein

(anti-drug antibodies [ADAs]).

Impact of immunogenicity on safety and efficacy

• Inhibition of the activity of the biologic (binding of ADAs to active site)

• Aberrant PK behavior (e.g. leading to more rapid clearance of the biologic)

• ADA cross-linked mAbs may act as a 'superagonist'

• Resistance to treatment with related products (reference product and biosimilar)

• T-cell-mediated hypersensitivity

• Immune complex-mediated reactions

• Hypersensitivity/ anaphylactoid reactions

• Infusion or injection site reactions

Neutralization

and/or

change in PK

Acute

reactions

Delayed

reactions

Cross-

reactivity (with endogenous

protein)

ImmunogenicityCross-

reactivity (with similar

biologics)

Safety Efficacy

Shankar et al. Nat Biotechnol 2007;25(5):555-561.EMA. Draft guideline on Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins (EMEA/CHMP/BMWP/14327/2006 Rev. 1). 2015.

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Biosimilars, are

SIMILAR to the original brand,

but NOT IDENTICAL.

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Establishment of regulatory biosimilar frameworks globally has increased – driven by WHO efforts

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Biosimilar

pathways

Biosimilar pathways

under developmentLaw in place

2016 (June) 2010

In general, regulators require:

– High degree of analytical similarity

– High degree of pre-clinical and clinical similarity

– Post-approval commitment to pharmacovigilance

Evolution of BS regulation in EEMEA in last 5 years

2010/11

2015

2+4

WHO. Guidelines on biosimilars 2009. http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdfEMA. Overaching guideline on biosimilars 2014: CHMP/437/04 Rev 1. EMA. Guideline on immunogenicity 2007: EMEA/CHMP/BMWP/14327/2006.

FDA. Guidance on biosimilarity 2015. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdfFDA. Guidance on quality 2015:Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product (PDF - 144KB)

FDA. Draft guidance, Q&A on BPCI Act 2015:Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 Guidance for Industry (PDF - 107KB)

Biosimilar regulatory framework comparison

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Regulatory

Framework

Similarity

concept

Substitution/

Interchange-

ability

ImmunogenicityNaming/

Pharmacovigilance

EMA

Concept created by EUDecided at member state level

and product

Needs to be studied in

humans pre and post

approval

EU uses INN system but

recommends additional use of

Trade Name to distinguish

Biotherapeutic

products

--------------

PV is required for all products

in EU, US and in accordance

with WHO guideline

-------------

Requires adequate monitoring

process to differentiate AEs in

the marketplace – but is not

specified

WHOFollows EU principles;

however, WHO has not

issued product specific non-

clinical or clinical guidelines

Not addressed in WHO guidance

FDA Similar concept to EU except

no product specific guidance.

Interchangeability is not

recommended

TOC

WHO-specific EMA-specific FDA-specific Common Guidance

Iran Regulatory framework

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Regulatory Framework

Similarity concept

Substitution/Interchangeability

ImmunogenicityNaming/

Pharmacovigilance

IFDA

Follows WHO principles Not addressed Not defined Not defined

• For some products in Iran, the typical stepwise approach demonstrating biosimilarity, including the conduct of sufficiently powered clinical trials in (an) appropriate patient population(s), using sensitive endpoint(s), is missing or non transparent. The “totality of the evidence” usually generated to establish biosimilarity compared to an RBP meeting WHO SBP guidelines* is not available or has significant gaps. Therefore, such products should not be regarded as equivalent to the respective RBP

• This is why these products are considered as non – comparable biologics• Physicians need to be informed about this and potential impact on patients safety

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IDF Releases Position Paper on Biosimilars in the Treatment of DM

• HCPs’ Recommendations:

HCPs should ensure that people with diabetes well managed on an existing insulin arenot changed to another insulin formulation, including biosimilars, without good clinicalreason and evidence of interchangeability.

HCPs should present the reasons and agree jointly with the diabetes patients on theappropriate use of biosimilar insulins, providing clear and sufficient information.

HCP should take in to consideration the person’s preference in the choice of biosimilarinsulins through individual features such as pen injectors for delivery.

HCPs should report any adverse reaction to a biosimilar insulin (as they would for otherinsulin formulations) so that appropriate monitoring can take place.

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IDF Releases Position Paper on Biosimilars in the Treatment of DM

• Pharmacists’ Recommendations:

Pharmacists should be well-informed about insulinformulations, including biosimilars.

Pharmacists should be in contact with the prescribingphysician in case of substituting the product, in order to trackthe assessment of the clinical outcomes.

NHS guideline for Biosimilar:

Automatic substitution at the pharmacy level without consulting theprescriber is not appropriate for biological medicines, includingbiosimilar medicines and is not permitted at this time.

Insulin products should be prescribed by the brand name.

Switching between insulin products has service workload implicationsand should only be carried out as part of a carefully planned program byspecialists.

Issues to consider when evaluating a biosimilar insulin or insulin analog

Issue Evaluate

Manufacturer• Reliability of supply• Stock position• Storage and Handling

Clinical efficacy• Clinical trials using different batches• Appropriate design• Batch Consistency

Clinical safety and tolerability

• PK/PD profile key for demonstrating comparability to reference product

• Safety and tolerability profiles compare to reference• Precautions or contraindications provided• Serious adverse event reporting• Immunogenicity• Mitogenicity• Post-marketing pharmacovigilance• Critical post individual dose response• Insulin administration devices precision

Price • Cost-Effectiveness

Ensuring – importance for the patients

Prescription from doctor Medication dispensed at

pharmacy

Patient’s life changes, e.g.

moves home and hospital

Patient experiences side

effects

Prescription?

Did the doctor prescribe the medication

by brand name or by international non-

proprietary name (INN)?

Substitution?

Did the pharmacist substitute the

original prescription with another

medicine?

Change of circumstances?

Is the patient being prescribed exactly the

same medicine as they were previously?

Adverse reaction?

How can the exact product which caused

the adverse drug reaction be identified?

The European Medicines Agency (EMA)

acknowledges that all appropriate

measures should be taken to ensure

traceability, including prescribing by

brand name.

The European Commission issued a

directive which requires the use of the

brand name when prescribing biologics.

This will ensure that automatic

substitution of a biosimilar does not

occur when the medicine is dispensed by

the pharmacist.

In order to improve traceability of

biologics, the brand name of the

administered product should be clearly

recorded (or stated) in the patient file.

Full traceability is important in case of

the occurrence of adverse reactions.

EMA. CHMP/437/04 Rev 1. 23 Oct 2014; EC. Directive 2010/84/EU. 15 Dec 2010; EC. Directive 2012/52/EC. 20 Dec 2012 [accessed Dec 2016].

Thank You for Your Attention!