Biosimilars, a Global Opportunity?

EU Perspective

Kyoto, 4-6 December 2012

IGPA Annual Conference 2012

Suzette Kox Senior Director Scientific Affairs, EGA, EU

What IS a

Biosimilar?

It is a successor to a licensed originator biological

product: “the reference product” (RP) and meeting

the highest regulatory standards (e.g. Japan, EU)

It has demonstrated high similarity in

physicochemical and biological characteristics,

efficacy and safety with the reference product,

based on a comprehensive and robust head-to-

head comparability exercise

It also means that there are no clinically

meaningful differences with the reference product

2

Approved Biosimilar (e.g. in EU)

Biosimilar and Reference Product

Super Imposable Results

Gel A Gel B

Brockmeyer C & Seidl A et al. Eur J Hosp Pharm Pract 2009;15:34–40

Sample 1(biosimilar) 2(reference) 3(biosimilar) 4(reference)

Comparison of isoform pattern for epoetin alfa

by isoelectric focusing gel electrophoresis

Example of a Biosimilar Filgrastim:

Highly Similar to Reference Product

Comparability performed for

EU Biosimilar application

showed highly similar results

with state of the art methods

Primary structure – peptide mapping Higher order structure – UV CD spectroscopy

Bioactivity – Surface plasmon resonance spectroscopy

With courtesy of Sandoz

What’s in the Name?

Terminology is important

• Inconsistency in nomenclature for

biosimilars has caused confusion

• Confusion is a potential concern for

patient safety and efficacy

• Confusion can lead to misconceptions

in published reports on apparent

problems with “biosimilars”

See R. Thorpe and M. Wadha in GABI Volume 1/2012/Issue 3-4

Slide © by Martina Weise, MD, BfArM, EGA 10th international biosimilars symposium, 20 April 2012 London

Innovation Required in Technical

and Clinical Development

Time &

investment

Clinical

development

• Significant expense (USD 75-250m)

• Long time to develop (7-10 years)

• Use of novel endpoints, novel biomarkers and

populations to confirm biosimilarity (not de novo

safety/efficacy)

• Clinical trial design to support extrapolation

across indications and interchangeability

Key challenges

Technical

development

• Achieving “highly similar” to match originator

molecule profile

• Matching final dosage form of originator

7

Target Directed Development and Confirmation of Biosimilarity

PK/PD

Preclinical

Biological

characterization

Physicochemical

characterization

Clinical

Reference

product

Purification process

development

Bioprocess development

Recombinant cell line development

Drug product

development

Target range

Process

development

Analytics

2. Confirmation

of biosimilarity

Leveraging biological variability

1. Target directed

development

8 Biosimilar development is fundamentally comparative

Slide © Sandoz

Global Reference Product Needed

– Repetition of studies are unnecessary, unethical and

uneconomical

– Reference products have been approved in different

regions based on the same data package (quality,

nonclinical, clinical) (global development /GD)

– Originator typically manufactures from single

location and master cell bank

– Reference products marketed in ICH regions and

beyond are highly comparable, thus sourcing is

possible for use in pivotal studies

9

Analytical methods are sensitive to differentiate between:

Batch to batch variation

Batches before and after a manufacturing process change

Batches from different sites

Discriminating Power of

Current Analytical Tools

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Analytical methods can

determine whether batches

sourced in different countries

are comparable

microheterogeneity of protein

structure

Purity profiles

Glycan distribution

Originator product batches

- G2F amounts

Expiry date

% G2F

Manufacturing

process

change

10

With courtesy of Sandoz

Confirmation in Europe: Cancer Drugs

Budgets are Doubling each 4 Years

Costs of anticancer

drugs, France:

2004 = 474 Million

Euros

2008 = 975 Million

Euros – Perrin S. Therapeutic

decision making in oncology.

Hospital Pharmacy Europe.

2010 (Sept/Oct);52:36-37

Slide © by Paul Cornes, MD

Growing Demand Threatens to

Limit Patient Access

0

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1963 1972 1980 1985 1990 1995 2004

Cancer US treatment spending, in billions (1963-2004)

US$

$1.3 $13.1

$27.5

$72.1

Slide © by Paul Cornes, MD, presented at 9th EGA annual international biosimilars symposium

14 April 2011 London

The World Spends More Each Year for

Cancer Treatment

Data: IMS

Global spend on oncology drugs: projected for 2010-12

Spend doubled in

4 years 2004-2008

Slide © by Paul Cornes, MD

June 2012: European Commission “We will accept that a biosimilar application contains data

from tests with reference products that are not sourced from

the EU. I am also able to inform you that this change of

interpretation is possible on the basis of the existing

legislation. It hence could be applied without awaiting a

lengthy legislative process. Obviously, this requires

appropriate conditions to ensure that the different reference

products in the EU and outside are comparable.”

Former EU Commissioner for Health and Consumer Protection

Dalli at EGA annual conference in Malta

EMA/940451/2011

EU: Non- EU Sourced

Reference Product

within Reach (1)

EU: Non- EU Sourced Reference Product within Reach (2)

September 2012:European Medicines Agency

“With the aim of facilitating the global

development of Biosimilars and to avoid

unnecessary repetition of clinical trials, the

European Commission has confirmed that it

intends to accept batches of reference

medicinal products sourced from outside the

EEA in certain pre-clinical and clinical

studies for the comparability exercise”.

EMA/940451/2011

EU: Non- EU Sourced Reference Product within Reach (3)

September 2012:European Medicines Agency

Under this approach, it will be the applicant's

responsibility to establish that the batches sourced

outside the EEA is representative of the reference

medicinal product authorised in the EEA through an

extensive analytical comparison”.

“A case by case approach would be required to

ascertain the suitability of batches of the non-EEA

sourced reference product and may require

comparative pharmacokinetic and

pharmacodynamics data”. EMA/940451/2011

Current Thinking for

Quality Data Package Submitted with Initial IND To support non-clinical and/or clinical studies using non US-licensed comparator, provide analytical similarity data from:

Biosimilar Product Clinical material or material manufactured at clinical scale

Ideally more than one lot

Combination of data from DP, DS and development lots

US-licensed reference Product Should provide data from more than one lot

Justification that designated reference material is representative

Non US-licensed Comparator Product Should provide data from more than one lot

Justification that designated reference material is representative

Biosimilar

Product

US-Licensed

Reference

Product

Non-

US Licensed

Comparator

Slide © by Steven Kozlowski, M.D. Director, Office of Biotechnology Products, GPhA Fall Technical Conf. 3 Oct. 2012

Current Thinking for

Quality Data Package Submitted with Initial

IND Specify if biosimilar product, US-licensed product and non-US comparator lots were analyzed side-by-side Expectation that many methods will be performed

side-by-side

Biosimilar product characterization and batch release data (separate from similarity study) Thorough characterization on at least reference

standard lot

Batch release data on all DS and DP lots

– Clinical and toxicology

Slide © by Steven Kozlowski, M.D. Director, Office of Biotechnology Products, GPhA Fall Technical Confference 3 Oct. 2012

US-EU Close

Collaboration

“With regard to the acceptance of US-sourced

reference medicinal products, a close collaboration

with the United States Food and Drug Administration

(FDA) is foreseen to ensure harmonisation of

requirements.

Details of the scientific requirements will be outlined

in the revised draft guideline on similar biological

medicinal products (CHMP/437/04).

will only enter into force after the revision of the

guideline

EMA/940451/2011

US-EU Harmonised Approach

to Global Development

Channels are open

via

EMA/FDA

‘biosimilars’

cluster meetings

EU-US High Level

Working Group on

jobs and growth on

regulatory issues

Impact on Rest of the World/Acceptance of

Non-Locally Sourced Reference Product Japan

ICH

country

The reference products should be drugs approved in Japan and be

the same product throughout the development period of the

biosimilar products

WHO Suggests establishing criteria to guide the use of a non-nationally

licensed reference product. RP should be authorized and widely

marketed in another jurisdiction with a well-established regulatory

framework and large experience with evaluating biological products

and pharmacovigilance activities

Canada Reference product not approved in Canada may be accepted on

request to the Minister or on recommendation by the Minister.

The sponsor is responsible for showing that the non-Canadian

reference biologic drug used for the purposes of demonstrating

similarity is a suitable proxy for the version of the product approved

in Canada.

Brazil If the reference product was not registered in Brazil, a new biological

product registered by another regulatory authority with similar

technical-scientific criteria as Anvisa’s shall be candidate for

comparator

Impact on Rest of the World/Acceptance of

Non-Locally Sourced Reference Product Argentina …..a biologic drug authorized by another Sanitarian Authority could be

considered for a Reference Product as long as it provides sufficient

specifications, characteristics of the product and experience and

knowledge of its use in the market.

Australia Fully adopted European Guideline on Similar Biological Medicinal

Products in 2008

New

Zealand

Non locally sourced reference product is acceptable only if public

domain information convincingly proves that its manufacturing sites

are the same as the ones registered in New Zealand. API and FDF

manufacturing sites are in the NZ public domain

Singapore Foreign reference product is acceptable only if public domain

information convincingly proves that its manufacturing sites are the

same as the ones registered in SG. Manufacturing sites are retrievable

from SG agency homepage for any product.

Malaysia A medicinal product registered in the reference countries (Australia,

Canada, EU (via centralised procedure), United Kingdom, France,

Japan, Sweden, Switzerland, USA is considered acceptable

APEC and Biosimilars

APEC Harmonization Center (AHC)

Biosimilars Workshop April 2012 Seoul

Sponsored by APEC Life Sciences

Innovation Forum Regulatory

Harmonization Steering Committee

KFDA: roadmap to achieve regulatory

regional harmonization of biosimilars

importance of using a single RP in the demon

stration of biosimilarity

Global Opportunity?

Yes!

EU-US harmonised requirements for GD

lay the basis for alignment of 3rd

countries

because scienced-based approach

no redundancy of Phase III trials

Experience shows that many countries

accept already today physico-chemical,

preclinical and clinical comparability

against a foreign reference product

Global Opportunity?

Yes!

US/EU: very important from a

regulatory-approval point of view also

for companies from emerging markets

Increasing demand for high quality

biosimilars worldwide

Biological sales off patent

$70 bn over the next 5 years

$100 bn by 2020

Thank you

ありがとうございます

Acronyms

APEC Asia-Pacific Economic Cooperation

DP Drug Product

DS Drug Substance

GD Global Development

IND Investigational New Drug

ICH International Conference on Harmonisation

EEA European Economic Area

EU European Commission

KFDA Korean Food and Drug Administration

RP Reference Product

US FDA United States Food and Drug Administration

WHO World Health Organisation