9 Karin Heidenreich - Novartis

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Dr. Karin Heidenreich / Global Public Policy R&D Novartis International AG, Switzerland Workshop on Biotherapeutics & Biosimilars Lima/Peru on 19 November 2013 Biosimilars: Principles of their Development and Evaluation

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Tuesday, 19 November, 2013 Latin America Biotherapeutic Conference Day 1

Transcript of 9 Karin Heidenreich - Novartis

Page 1: 9 Karin Heidenreich -  Novartis

Dr. Karin Heidenreich / Global Public Policy R&D

Novartis International AG, Switzerland

Workshop on Biotherapeutics & Biosimilars

Lima/Peru on 19 November 2013

Biosimilars: Principles of their Development and Evaluation

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Disclaimer

The following presentation contains forward-looking statements that can be identified by terminology such as such as “potential,”

“expected,” “will,” “planned,” or similar expressions, or by express or implied discussions regarding potential new products, potential new

indications for existing products, or regarding potential future revenues from any such products; potential outcomes of our efforts to

improve the quality standards at any or all of our manufacturing sites; or regarding potential future sales or earnings of the Group or any

of its divisions in the near- and long-term; or by discussions of strategy, plans, expectations or intentions. You should not place undue

reliance on these statements. Such forward-looking statements reflect the current views of the Group regarding future events, and involve

known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results,

performance or achievements expressed or implied by such statements. There can be no guarantee that any new products will be

approved for sale in any market, or that any new indications will be approved for any existing products in any market, or that any

approvals which are obtained will be obtained at any particular time, or that any such products will achieve any particular revenue levels.

Nor can there be any guarantee that the Group will be successful in its efforts to improve the quality standards at any or all of our

manufacturing sites, or that we will succeed in restoring or maintaining production at any particular sites. Neither can there be any

guarantee that the Group, or any of its divisions, will achieve any particular financial results, either in the near-term or in the long-term. In

particular, management's expectations could be affected by, among other things, unexpected regulatory actions or delays or government

regulation generally; unexpected clinical trial results, including additional analyses of existing clinical data or unexpected new clinical

data; the Group's ability to obtain or maintain patent or other proprietary intellectual property protection, including the ultimate extent of the

impact on the Group of the loss of patent protection on key products which commenced last year and will continue this year; unexpected

product manufacturing and quality issues, including the potential outcomes of our efforts at the Sandoz and Alcon sites that are subject to

Warning Letters, and with respect to our efforts to restart production of products formerly produced at the Consumer Health manufacturing

facility at Lincoln, Nebraska; government, industry, and general public pricing pressures; uncertainties regarding actual or potential legal

proceedings, including, among others, actual or potential product liability litigation, litigation and investigations regarding sales and

marketing practices, shareholder litigation, government investigations and intellectual property disputes; competition in general;

uncertainties regarding the effects of the ongoing global financial and economic crisis, including the financial troubles in certain Eurozone

countries; uncertainties regarding future global exchange rates; uncertainties regarding future demand for our products; uncertainties

necessarily involved in long-term financial projections; uncertainties involved in the development of new healthcare products; the impact

that the foregoing factors could have on the values attributed to the Group's assets and liabilities as recorded in the Group's consolidated

balance sheet; and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange

Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual

results may vary materially from those described herein as anticipated, believed, estimated or expected. Novartis is providing the

information in this presentation as of this date and does not undertake any obligation to update any forward-looking statements as a result

of new information, future events or otherwise.

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Table of Contents

Key Principles of Biosimilar development

• What is a Biosimiliar?

• Differences to Generic Medicines

• Development via a Two-Step Procedure

Overview of international Guidance on Biosimilars

Novartis Position on Biosimilars

Summary and Regulatory Needs

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Table of Contents

Key Principles of Biosimilar development

• What is a Biosimiliar?

• Differences to Generic Medicines

• Development via a Two-Step Procedure

Overview of international Guidance on Biosimilars

Novartis Position on Biosimilars

Summary and Regulatory Needs

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Different types of biologics in circulation Not every version of a biologic is a biosimilar

Originator Biosimilar Non-

comparable

Counterfeit

medicine

• First registration

of new molecule

• Approval based

on demonstrated

quality, safety

and efficacy

• Version of

registered original

biologic

• Approval based on

extensive

comparability

exercise via special

and stringent

registration pathway

(e.g. in EU)

• Patients can expect

same clinical profile

as with originator

• Questionable copy

of registered original

biologic

• Approval not based

on demonstrated

comparability

without special

registration pathway;

sometimes stand-

alone application

• Patients cannot

expect the same

clinical profile as

with originator

• Illegal copy version

of registered

original biologic

• Biological and

pharmaceutical

quality unclear,

mostly substandard

or even harmful

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Different types of biologics in circulation Not every version of a biologic is a biosimilar

Originator Biosimilar Non-

comparable

Counterfeit

medicine

• First registration

of new molecule

• Approval based

on demonstrated

quality, safety

and efficacy

• Version of

registered original

biologic

• Approval based on

extensive

comparability

exercise via special

and stringent

registration pathway

(e.g. in EU, USA,

Canada, Australia)

• Patients can expect

same clinical profile

as with originator

• Questionable copy

of registered original

biologic

• Approval not based

on demonstrated

comparability

without special

registration pathway;

sometimes stand-

alone application

• Patients cannot

expect the same

clinical profile as

with originator

• Illegal copy version

of registered

original biologic

• Biological and

pharmaceutical

quality unclear,

mostly substandard

or even harmful

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What is a Biosimilar?

Definition proposed by EMA in draft guideline on „similar biological medicinal products‟1:

A biosimilar is a biological medicinal product containing a version of the active substance of an already authorised original biological medicinal product (reference medicinal product).

A biosimilar demonstrates similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise.

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1 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/05/WC500142978.pdf

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Differences between Generics and Biosimilars

Same qualitative and quantitative composition in active substances and the same pharmaceutical form as the referenced originator product

Abbreviated dossier: own quality information, demonstrated bioequivalence as well as referring to the established safety and efficacy data of the reference product

Generics and reference product are usually interchangable/substitutable

A version of the active substance of an already authorized original biological medicinal product

Demonstrates similarity to the reference product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise

Patients can expect the same clinical outcomes from a biosimilar and the originator drug

Expiry of patent and

other exclusivities

Small

molecules

Original

biologics

Generics Biosimilars

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Development of high-quality biosimilars is a systematic and robust process with two key steps

Phase I Phase III

Develop highly similar product Confirm biosimilarity

Drug substance

Formulation / Drug product

GLP Tox.

Process validation

Technical development to achieve a

“highly similar” molecule, which

matches the quality attributes of the

reference product

Demonstration of structural and

functional similarity

Targeted non-clinical and clinical

program to demonstrate similarity

Scope depends on similarity in quality

attributes and requires agreement

with health authorities

Step 1 Step 2

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Step 1: Variability of the reference product defines the target

Manufacturing changes lead to

more pronounced shifts

• Manufacturing changes are made

frequently

• Changes in the manufacturing process

generate slightly different versions of the

originator molecule

• These shifts usually have no implication

for clinical function

• Non-identicality is a normal principle in

glycosylated proteins

• No batch of any biologic is “identical” to

the other batches

• Low variability is natural and generally not

problematic for clinical outcome

Biologic products vary from batch

to batch

Batch of drug substance (DS)

Bio

log

ica

l Activity (

Units/m

g)

0,0

0,4

0,8

1,2

1,6

2,0

08.2007 12.2008 05.2010 09.2011

Expiry Date

Unfucosylated G0

[% of glycans]

60

80

100

120

140

08.2007 12.2008 05.2010 09.2011

Expiry Date

ADCC Potency

[% of reference] Post-

Shift

Pre-Shift

Pre-Shift

Post-

Shift

Schneider, C. K.: Biosimilarity: A better definition of terms and

concepts. 25th Annual DIA EuroMeeting, 04-06/03/2013, Amsterdam

Schiestl, M., et al.: Acceptable Changes in Quality Attributes of Glycosylated

Biopharmaceuticals. Nature Biotechnology, 29 (4): 310-312, 2011

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Biosimilars are approved biologics with comparable Q, S and E to a reference product

Sample E IA IB IIA IIB IIIA IIIB IV V VII VIII E

Schellekens H et al. Eur J Hosp Pharm Pract 2004;3:43–7

Non-comparable “copy biologic” ≠ biosimilar

NOT similar to Reference E

Brockmeyer C & Seidl A et al. Eur J Hosp Pharm

Pract 2009;15:34–40

Approved biosimilar in EU

Sample 1 2 3 4

NO difference to originator

• Developed and manufactured using state-of-the-

art technology

• Demonstrated comparable quality (Q), safety (S),

and efficacy (E) to a reference product

• Approved via stringent regulatory pathways

• Non-comparable or alternative copy biologics are

NOT biosimilars

• Have not demonstrated biosimilarity via a state-

of-the-art comparability exercise

• Not approved following a specific biosimilars

registration pathway (e.g. in line with WHO

recommendations)

What is a biosimilar?

What is NOT a biosimilar?

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Step 2: Demonstration that no meaningful difference in clinical profile can be expected

Targeted non-clinical and clinical program with indication and endpoints most sensitive to detect differences; no re-demonstration of safety and efficacy

Extrapolation to other indications of the reference product should be possibile and justified based on the “Totality-of-Evidence”, including:

• High level of structural (as demonstrated by physicochemical characterization) and functional (as demonstrated by in vitro biological assays) similarity

• Similarity regarding pharmacokinetics in humans

• Similar efficacy and safety in a single, most sensitive indication (immunogenicity)

• Same mode-of-action of indications (if known)

Immunogenicity data should be always required for all biologics, including biosimilars

Risk management plans for post-licensing surveillance should be routinely required for all new drugs, including biosimilars

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Illustration of the difference between originator and biosimilar development

The world

turned upside

down....

Originator

development

Biosimilar

development

Clinical

studies

PK/PD

Non-clinical

Analytical Analytical

Non-clinical

PK/PD

Additional clinical studies

Source: modified slide shown by EGA at EMA Workshop in London on 31 Oct 2013

Comparison

with the

reference

product

Main focus of the originator development program is on clinical studies; for the

biosimilars on the analytical studies

The purpose of the clinical program of the biosimilar is to confirm similarity of

efficacy and safety to the reference product, not to re-establish efficacy and safety

Therefore, design and endpoints of the clinical studies conducted with the

biosimilar are different

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Table of Contents

Key Principles of Biosimilar development

• What is a Biosimiliar?

• Differences to Generic Medicines

• Development via a Two-Step Procedure

Overview of international Guidance on Biosimilars

Novartis Position on Biosimilars

Summary and Regulatory Needs

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Provides globally acceptable principles1 for licensing of biotherapeutic products that are claimed to be similar to original biotherapeutic products:

• “A SBP is intended to be similar to a licensed biotherapeutic product for which there is a substantial evidence of safety and efficacy. The ability for the SBP to be authorized based on reduced non-clinical and clinical data depends on proof of its similarity to an appropriate RBP through the comparability exercise.”

• “Comprehensive characterization and comparison at the quality level are the basis for possible data reduction in the non-clinical and clinical development.”

• “Significant differences between the SBP and the chosen RBP detected during the comparability exercise would be an indication that the products are not similar and more extensive non-clinical and clinical data may be required to support the application for licensing.”

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WHO – 2009 Guidelines on evaluation of similar biotherapeutic products (SBPs)

1 http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf

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European Medicines Agency: Well-established regulatory framework for biosimilars (2005)

Legal basis

• Directive 2001/83/EC as amended, Art 10(4)

• Multiple general and product specific guidelines that are regularly updated (refer to next slide)

Main principles

• Regulatory pathway structured like the process to approve originators after significant manufacturing change

• Two-step approach to demonstrate similarity to reference product

• Extrapolation across indications possible under justified conditions

• Use of non-European reference product for partial demonstration of similarity based on bridging studies

• Acceptance of same INN and a label that allows the healthcare professional to make a treatment decision

• No statement on interchangeability/substitutability; competence with the national governments

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European Medicines Agency EU Guidelines for Biosimilars

General Other Product-specific

Quality

Non-clinical

Clinical

“Overarching”

Risk Management

Plan

Immunogenicity

assessment of

biotech products

Somatropin

Epoetin

G-CSF

Insulin

LMWH

Interferon alfa

G-CSF: Granulocyte-colony stimulating factor (filgrastim or lenograstim); LMWH: Low Molecular Weight Heparin; *Concept paper

Monoclonal

Antibodies

Interferon beta

Follicle Stimulation

Hormone

Statistical methods

for comparability in

quality attributes*

General Biosimilar

Brochure

Q&A Document

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US Food and Drug Administration

Legal basis

• Patient Protection and Affordable Care Act (Affordable Care Act), of 2010

• Biologics Price Competition and Innovation Act (BPCI Act) creates an abbreviated licensure pathway for biological products that are demonstrated to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product

• A number of (draft) guidance documents1

Main principles

• Licensed biosimilar and interchangeable biological products will have to meet the Agency‟s exacting standards of safety and efficacy

• Risk-based “totality-of-the-evidence” approach in support of a determination of biosimilarity of the proposed product to the reference product via a stepwise approach in the development of biosimilar products

• Distinction of „biosimilar products‟ and „interchangeable biosimilar products‟

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1 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologic

Applications/Biosimilars/

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Table of Contents

Key Principles of Biosimilar development

• What is a Biosimiliar?

• Differences to Generic Medicines

• Development via a Two-Step Procedure

Overview of international Guidance on Biosimilars

Novartis Position on Biosimilars

Summary and Regulatory Needs

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Novartis develops both, innovative medicines and biosimilars of high quality

Environment Patient needs Novartis portfolio

Pharmaceuticals

Vaccines and

Diagnostics

Sandoz (Generics) Full range

of healthcare options

Innovative medicines

Prevention

Affordable options

Self-care

Alcon

(Eye care)

OTC

Animal Health

Generics

and

Biosimilars

Innovative

Medicines

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Novartis Position on Biosimilars – Principles 1-4

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Biosimilars are

biologics

Biosimilars should be subject to the same requirements as any

other biologics of the same class

Interchangeability A biosimilar that has been registered via a robust regulatory

pathway has demonstrated to have the same clinical profile

as the reference product

Step-wise

development

of biosimilars

Biosimilar development programs should follow step-wise approach

and be scientifically sound

Extrapolation of

indication possible

Extrapolation of indication should be allowed if scientifically

justified, i.e. if „totality-of-evidence‟ has been demonstrated

For details please refer to: http://www.novartis.com/downloads/corporate-responsibility/resources/positions/biosimilars-science-based-

approval-sustainable-market-access.pdf

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Novartis Position on Biosimilars – Principles 5-8

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Same INN for

biosimilars

Biosimilar and reference product should have the same INN if the

molecular characteristics of the biosimilar are within the reference

product‟s range of variability and comparable safety and efficacy

have been shown

Fair competition

in the market

Novartis supports both, the promotion of innovation and the

possibility of fair competition by biosimilar products following

loss of exclusivity

Same pharmaco-

vigilance for

biosimilars

Robust and adequate pharmacovigilance measures needed for all

medicinal products based on their individual risk profile

High registration

standards

for biosimilars

Local approval requirements need to ensure high standards of

comparability between reference and biosimilar products

For details please refer to: http://www.novartis.com/downloads/corporate-responsibility/resources/positions/biosimilars-science-based-

approval-sustainable-market-access.pdf

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Table of Contents

Key Principles of Biosimilar development

• What is a Biosimiliar?

• Differences to Generic Medicines

• Development via a Two-Step Procedure

Overview of international Guidance on Biosimilars

Novartis Position on Biosimilars

Summary and Regulatory Needs

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Summary – Biosimilars...

... are successors to a biologic medicine that has been marketed based on a full registration dossier and has lost its exclusivity

... are not simple generics due to their complexity in terms of size, structure and manufacturing and therefore require a specific registration pathway

... have demonstrated similarity to the reference product via a two-step comparability procedure:

a. Analytical investigation to demonstrate structural and functional similarity

b. Targeted non-clinical and clinical trials to confirm similarity - de novo proof of efficacy not necessary

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Biosimilars should be approved according to specific, highly stringent regulations

High-quality biosimilars are safe treatment options and have the same issues as all other biologics, but do not generate more concerns

The quality standards for biosimilars should be the same as for original biologics

Biosimilars should be evaluated according to rigorous guidelines1, and must have

• Highly comparable structural and functional attributes

• No clinically relevant differences

Products that do not meet these high standards for similar biological products should not be approved and not put in circulation

A robust pharmacovigilance system should be in place to support patient safety with all medicinal products

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1 Refer to guidance from WHO, EMA and/or FDA