Biosimilars, a Global Opportunity? EU Perspective › igpa2012 › common › pdf › presentation...
Transcript of Biosimilars, a Global Opportunity? EU Perspective › igpa2012 › common › pdf › presentation...
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
0
10
20
30
40
50
60
01.2007 02.2008 03.2009 05.2010 06.2011
EU Lyo
0
10
20
30
40
50
60
01.2007 02.2008 03.2009 05.2010 06.2011
EU Lyo
EU Liq
0
10
20
30
40
50
60
01.2007 02.2008 03.2009 05.2010 06.2011
US Liq
EU Lyo
EU Liq
0
10
20
30
40
50
60
01.2007 02.2008 03.2009 05.2010 06.2011
US Lyo
US Liq
EU Lyo
EU Liq
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
10
20
30
40
50
60
70
80
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