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PAVING THE PATHWAY INTO US BIOSIMILARS MARKET: UPDATE OF USFDA BIOSIMILAR GUIDELINES
(AND HOW TO POTENTIALLY DUPLICATE
SANDOZ'S SUCCESS)
Alan Liss, Ph.D. (FDA ret) Principal Consultant, GXP farma, LLC
Biologics World Korea 2015 (9 - 10 June)
Seoul, Korea
1) Update on USBPCIA regulations
2) Putting BPCIA in context
3) How traditional Generics affect
biosimilars
4) As a business model, is it worth it?
Paving the pathway into US biosimilars market: Update of USFDA biosimilar guidelines
Rank Commodityname 2013
(billion$)
Annual
growth(%)
Category Main indications Company
1 Humira 10.4 19% biologics Rheumatoid arthritis Abbott
2 Seretide 8.7 9% Low molecular weight
compound
asthma GSK
3 Enbrel 8.6 10% biologics Rheumatoid arthritis,
psoriasis
Pfizer
4 Crestor 8.1 6% Low molecular weight
compound
hypercholesterolemia AstraZeneca
5 Remicade 7.8 9% biologics Rheumatoid arthritis,
Crohn'sdisease
Johnson
6 Nexium 7.6 14% Low molecular weight
compound
gastrohelcoma AstraZeneca
7 Abilify 6.6 30% Low molecular weight
compound
depression Bristol-Myers
Squibb
8 Lantus 5.9 8% biologics diabetes Aventis
9 Avastin 5.8 8% biologics Rectal oncology Roche
10 Herceptin 5.6 7% biologics Breast Cancer Roche
11 Mabthera 5.6 13% biologics lymphoma Roche
12 Cymbalta 5.2 5% Low molecular weight
compound
depression Lilly
13 Spiriva 4.8 8% Low molecular weight
compound
COPD Boehringer
Ingelheim
14 Lyrica 4.2 11% Low molecular weight
compound
Seizure,fibromyalgia Pfizer
15 Copaxone 4.2 21% biologics Relapsing-Remitting
MultipleSclerosis
Teva
TOP MONEY MAKERS IN THE GLOBAL BIO-PHARMA MARKET (Q2 2013)
Chemical Medicines Are Made; Biologics Are Grown
Chemical medicines are
chemicals made by chemists out
of other chemicals. That’s why
they are also known as “small
molecules” or “chemically-
synthesized drugs”
Following the same “recipe”
Biologics are grown from living things
A biologic must be manufactured under precise conditions, following many exacting steps, to yield a consistent product
Biologics are highly sensitive to manufacturing conditions
yields exactly the same
product
4 AbbVie | © 2013
When Do You Expect Approval of the First Biogeneric Drug?
6
12
24
58
0 10 20 30 40 50 60 70
Never
1 - 3 Years
4 - 7 Years
8 - 15 Years
Tim
efr
am
e
Percent
•BioPharm International, 9-2003
Biogenerics will appear in the
marketplace, at this time…
BPCIA
6
Scientific basis for “abbreviated” biosimilar pathway Demonstrate Quality, Safety, Efficacy
New Biologic Surveillance Regulatory Approval Quality Clinical
Non- clinical
Biosimilar Surveillance
Quality Extensive
Comparison to
Reference Abbreviated Non-clinical and Clinical Pathway
Clinical Compar- ability
Non clinical Regulatory
Approval
12 AbbVie | © 2013
8
FDA Draft Guidance Documents Give Additional Insight for Developers of All Biologics
FDA Draft Guidance Documents Give Additional Insight for Developers of All Biologics
Biosimilar Guidance Scientific
Considerations in Demonstrating Biosimilarity to a Reference Product Quality Considerations
in Demonstrating Biosimilarity to a Reference Protein Product Biosimilars Questions and Answers Regarding Implementation of the BPCIA of 2009
Key Takeaway Points FDA takes a fundamentally science-based approach, but does not address
interchangeability as a scientific matter
FDA describes 351(k) pathway as “abbreviated,” but it is unclear whether
pathway will reduce time or trial investment
FDA is interested in reviewing data developed with an ex-US reference product Is limited to analytical studies, addressing the applicability of FDA regulatory
initiatives such as quality-by-design and comparability for biosimilars
Discusses the regulatory history of comparability as well as biological products
historically regulated as drugs by the “505” pathway that will transition to regulation via the “351” pathway in 2020 Contains proposed answers to common questions, many of which were raised
by prospective sponsors at the Part 15 Public Hearing in November 2010
Broadly supports the more systematic advice given in the other two guidances,
and explicitly addresses additional issues such as delivery devices for biosimilars and timelines for requesting meetings with the Agency
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/Therapeutic BiologicApplications/Biosimilars/
These documents share the FDA’s current thinking on the development pathway for biosimilar
products, however they are not binding and sponsors may take a modified approach BPCIA: Biologics Price Competition and Innovation Act; part of the Patient Protection and Affordable Care Act of 2010 For more information:
KEY FDA GUIDANCES
10
•Scientific Considerations in Demonstrating Biosimilarity to a Reference Product; Guidance for
Industry (PDF - 169KB)
CDER/CBER, April 2015
•Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a
Reference Product; Guidance for Industry (PDF - 144KB)
CDER/CBER, April 2015
•Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price
Competition and Innovation Act of 2009 Guidance for Industry (PDF - 107KB)
CDER/CBER, April 2015
•Reference Product Exclusivity for Biological Products Filed Under; Draft Guidance (PDF -
99KB)
CDER/CBER, August 2014
•Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference
Product; Draft Guidance (PDF - 142KB)
CDER/CBER, May 2014
•Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants;
Draft Guidance (PDF - 272KB)
CDER/CBER, March 2013
•Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price
Competition and Innovation Act of 2009; Draft Guidance (PDF - 177KB)
CDER/CBER, February 2012
Overarching and Other biosimilar guidelines EMEA
11
Similar biological medicinal products
Overview of comments Adopted guideline Draft guideline Concept paper
CHMP/437/04 Rev. 1
October 2014
30 April 2015
Similar biological medicinal products
Adopted guideline
CHMP/437/04
September 2005
October 2005
Revision of the guideline on immunogenicity assessment ofbiotechnology-derived therapeutic proteins
Concept paper EMA/275542/2013
Released for consultation March 2014
Deadline for comments 30 June 2014
Similar biological medicinal products containingbiotechnology-derived proteins asactive substance: non-clinical and clinical issues
Adopted guideline Draft guideline Concept paper
EMEA/CHMP/BMWP/42832/2005 Rev. 1
January 2015
July 2015
Similar biological medicinal products containingbiotechnology-derived proteins asactive substance: non-clinical and clinical issues
Adopted guideline
EMEA/CHMP/BMWP/42832/2005
February 2006
1 June 2006
Similar biological medicinal products containingbiotechnology-derived proteins asactive substance: quality issues
Overview of comments Adopted guideline Draft guideline Concept paper
EMA/CHMP/BWP/247713/2012
June 2014
1 December 2014
Similar biological medicinal products containingbiotechnology-derived proteins asactive substance: quality issues
Adopted guideline
EMEA/CHMP/BWP/49348/2005
February 2006
1 June 2006
mmunogenicity assessment of monoclonal antibodies intended for in vivo clinical use
Overview of comments Adopted guideline Draft guideline Concept paper
EMA/CHMP/BMWP/86289/2010
June 2012
1 December 2012
Comparability of biotechnology-derived medicinal products after a change in the manufacturing process - non-clinical and clinical issues
Adopted guideline Draft guideline Concept paper
EMEA/CHMP/BMWP/101695/2006
July 2007
November 2007
Immunogenicity assessment ofbiotechnology-derived therapeutic proteins
Adopted guideline Draft guideline Concept paper
EMEA/CHMP/BMWP/14327/2006
January 2008
April 2008
Comparability of medicinal products containingbiotechnology-derived proteins asactive substance - Quality issues
Adopted guideline
CPMP/ICH/5721/03
December 2003
December 2003
Superseded byCPMP/ICH/5721/03
Comparability of medicinal products containingbiotechnology-derived proteins as drug substance: non-clinical and clinical issues
Adopted guideline
EMEA/CPMP/3097/02
December 2003
June 2004
Superseded byCHMP/BMWP/101695/06
Development of a Committee for Proprietary Medicinal Productsguideline on comparability ofbiotechnology-derived products
Concept paper CPMP/BWP/1113/98
June 1998
Product-specific biosimilar guidelines EMEA
12
Similar biological medicinal products containing recombinant follicle-stimulating hormone
Overview of comments Adopted guideline Draft guideline Concept paper
CHMP/BMWP/671292/2010
March 2013
1 September 2013
Similar biological medicinal products containing interferon beta
Overview of comments Adopted guideline Draft guideline Concept paper
CHMP/BMWP/652000/20100
March 2013
1 September 2013
Similar biological medicinal products containing monoclonal antibodies: non-clinical and clinical issues
Overview of comments Adopted guideline Draft guideline Concept paper
EMA/CHMP/BMWP/403543/2010
June 2012
1 December 2012
Similar biological medicinal products containing recombinant erythropoietins
Overview of comments Adopted guideline Draft guideline Concept paper
EMEA/CHMP/BMWP/301636/08
April 2010
30 September 2010
Annex to guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues - Guidance on similar medicinal products containing recombinant erythropoietins
Submission of comments Adopted guideline
EMEA/CHMP/945626/2005
March 2006
July 2006
Superseded byEMEA/CHMP/BMWP/301636/08
Non-clinical and clinical development of similar biological medicinal products containing low-molecular-weight heparins
Draft guideline Concept paper
EMEA/CHMP/BMWP/118264/2007 Rev. 1
Released for consultation January 2013
Deadline for comments 31 July 2013
Similar biological medicinal products containing low-molecular-weight heparins
Overview of comments Adopted guideline Draft guideline Concept paper
EMEA/CHMP/BMWP/118264/2007
April 2009
October 2009
Non-clinical and clinical development of similar medicinal products containing recombinant interferon alpha
Adopted guideline Draft guideline Concept paper
EMEA/CHMP/BMWP/102046/2006
June 2009 April 2009
Annex to guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues - Guidance on biosimilar medicinal products containing recombinant granulocyte-colony stimulating factor
Adopted guideline EMEA/CHMP/BMWP/31329/2005
February 2006 June 2006
Annex to guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues - Guidance on similar medicinal products containing somatropin
Adopted guideline EMEA/CHMP/BMWP/94528/2005
February 2006 June 2006
Revision of the guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant human insulin and insulin analogues
Overview of comments Adopted guideline Second draft guideline First draft guideline Concept paper
EMEA/CHMP/BMWP/32775/2005 Rev. 1
March 2015 September 2015
Annex to guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues - Guidance on similar medicinal products containing recombinant human insulin
Adopted guideline EMEA/CHMP/BMWP/32775/2005
February 2006 June 2006
1) Update on USBPCIA regulations
2) Putting BPCIA in context
3) How traditional Generics affect
biosimilars
4) As a business model, is it worth it?
Paving the pathway into US biosimilars market: Update of USFDA biosimilar guidelines
PROTEINS BIOLOGICS
Comparability Across the
Spectrum of Protein Products
15
Most Biotech
Products:
Characterization
(Animal Studies)
PK(PD)
Simple Products:
Characterization
(Animal Studies)
Highly Complex
Products:
Characterization
(Animal Studies)
PK(PD)
Limited Purpose
Clinical Studies
Approved changes have occurred
during product development scale-up
Approved changes have occurred
during inter- and intra-company tech transfer
BIOLOGICS
COMPARABILITY
Product Comparability Why does it matter?
• In general, each license is for one product produced by one manufacturing process
• Data from different manufacturing facilities, or the same facility using different processes, cannot be used to support the same BLA unless comparability is demonstrated
• Comparability is demonstrating that critical product characteristics including safety, purity, and potency have not changed even when the manufacturing process has changed
The Immunogenicity Barrier The Critical Path Initiative: The Division of Therapeutic Proteins’ Perspective
Amy S. Rosenberg, MD
Director, Division of Therapeutic Proteins
ACPS Meeting, October 19, 2004
19
Medicine name Active substance Manufacturer Status Year of authorization/ withdrawal/refusal
Omnitrope® Somatropin Sandoz GmbH Authorized 2006 Valtropin® Somatropin BioPartners GmbH Withdrawn 2006 Alpheon RecombinantHuman Interferon 𝛼-2a BioPartners GmbH Refused 2006 Abseamed® Epoetin 𝛼 Medice Arzneimittel Pütter GmbH&Co.KG Authorized 2007 Binocrit® Epoetin 𝛼 Sandoz GmbH Authorized 2007 EpoetinAlphaHexal® Epoetin 𝛼 Hexal AG Authorized 2007 RetacritTM EpoetinZeta Hospira UK Ltd Authorized 2007 Silapo® EpoetinZeta Stada Arzneimittel AG Authorized 2007 Biograstim® Filgrastim AbZ-Pharma GmbH Authorized 2008 Filgrastimratiopharm® Filgrastim Ratiopharm GmbH Withdrawn 2008 Ratiograstim® Filgrastim Ratiopharm GmbH Authorized 2008 Tevagrastim® Filgrastim Teva GmbH Authorized 2008 FilgrastimHexal® Filgrastim Hexa lAG Authorized 2009 Zarzio® Filgrastim Sandoz GmbH Authorized 2009* NivestimTM Filgrastim Hospira UKLtd. Authorized 2010 Grastofil Filgrastim Apotex EuropeB.V. Authorized 2013 Ovaleap® Follitropin 𝛼 Teva PharmaB.V. Authorized 2013 InflectraTM Infliximab HospiraUKLtd Authorized 2013 RemsimaTM Infliximab Celltrion Healthcare HungaryKft. Authorized 2013 Bemfola Follitropin 𝛼 Finox BiotechAG Authorized 2014 Abasria® Insulinglargine Eli Lilly and Company and Boehringer Ingelheim Authorized 2014
BIOSIMILARS IN EUROPE
* The first “official” biosimilar in US-2015
1) Update on USBPCIA regulations
2) Putting BPCIA in context
3) How traditional Generics affect
biosimilars
4) As a business model, is it worth it?
Paving the pathway into US biosimilars market: Update of USFDA biosimilar guidelines
Requirements for generic (small molecule) approval
• Same active ingredient(s)
• Same route of administration
• Same dosage form
• Same strength
• Same conditions of use
Compared to reference listed drug (RLD) - (brand name product)
Transfer of Therapeutic Products to the Center for
Drug Evaluation and Research (CDER)
22
On June 30, 2003, FDA transferred some of the therapeutic biological
products that had been reviewed and regulated by the Center for
Biologics Evaluation and Research (CBER) to the Center for Drug
Evaluation and Research (CDER). CDER now has regulatory
responsibility, including premarket review and continuing oversight, over
the transferred products. In regulating the products assigned to them,
CBER and CDER will consult with each other regularly and whenever
necessary.
On October 1, 2003, the staff comprising CBER's Office of Therapeutics
Research and Review also transferred to CDER. CDER created two new
offices to accommodate the former CBER staff:
•The Office of Drug Evaluation VI, within CDER's Office of New Drugs,
and
•The Office of Biotechnology Products, within CDER's Office of
Pharmaceutical Science.
NCTR CBER CDRH
CFSAN CVM
Food and Drug Administration
Center for Drug Evaluation
and Research
CDER
ORA
Leading countries in terms of pipeline and marketed
biosimilars
Leading countries for biosimilars and copy-biologics, by stage of development, 2011
Source: Datamonitor; company-reported information, 2011
In terms of pipeline and marketed copy-
biologics, India leads the way with 102
products (encompassing 27 molecules),
closely followed by China with 50 products
(25 molecules), largely driven by the
development of cheap simple biologics
approved by regulatory authorities in
these markets as new drugs.
The EU is the market with the greatest
number of pipeline and marketed
biosimilar products, totaling 66 (32
molecules) as of December 2011,
reflecting the fact that the European
Medicines Agency (EMA) was the first
developed market to introduce a
biosimilars approval pathway in 2005.
South Korea and the US also have sizable
biosimilar pipelines.
0
20
40
60
80
100
120
India
EU
China
Sou
th K
orea U
S
Arg
entin
a
Japa
n
Rus
sia
Mex
ico
Brazil
Oth
er
Nu
mb
er
of
ca
nd
ida
tes
Planned Development Pre-clinical
Clinical trials/ Pre-approval Approved / Launched biosimilars Approved / Launched copy biologics
Quality of Generic Manfacturers
25
Warning Letter Issued To Date Warning
Letter Issued
In Focus
Apotex Research Private
Limited
01/30/2015 Here
Micro Labs Limited 01/09/2015 Here
Cadila Pharmaceuticals Limited 10/15/2014 Here
Marck Biosciences Ltd. 07/08/2014 Here
Apotex Pharmachem India Pvt
Ltd.
06/17/2014 Here
Sun Pharmaceutical Industries 05/07/2014 Here
Canton Laboratories Private
Limited
02/27/2014 Here
USV Limited 02/06/2014 Here
Wockhardt Limited 11/25/2013 Here
Agila Specialties Private Limited 09/09/2013
Posh Chemicals Private Limited 08/02/2013 Here
Aarti Drugs Limited 07/30/2013
Wockhardt Limited 07/18/2013 Here
Fresenius Kabi Oncology Ltd 07/01/2013 Here
RPG Life Sciences Limited 05/28/2013 Here
26 - See more at: http://www.raps.org/Regulatory-Focus/News/2014/08/19/18980/Indias-Data-Integrity-Problems-
Updated-17-June-2014/#sthash.Pe2mBjsN.dpuf
BAGGAGE! Major Areas of GMP Concerns
• According to statistical data based on foreign inspection observations,
the following are the top 15 major areas of GMP deficiencies for 2008 to 2014 (2):
• Quality system elements/procedures documentation
• Design and maintenance of premises
• Design and maintenance of equipment
• Process validation
• Procedures and facilities sampling
• Manufacturing documentation issue (falsification)
• Potential for microbiological contamination
• Specification and testing documentation
• Facilities and equipment status labeling
• Environmental monitoring
• Supplier and contractor audit and technical agreements
• Equipment validation
• Hygiene/clothing
• Duties of key personnel
• Potential for chemical/physical contamination.
• Energy conservation (Many of the API producers in China consider it acceptable
to shutdown their clean utilities at night and restarting them in the morning without considering of the impact on the
environmental conditions of these systems [e.g., bioburden]).
FDA approves first biosimilar Zarxio TM
• Sandoz is the first company to receive approval of a biosimilar in the US through the
• new FDA biosimilars pathway established under BPCIA
• Zarxio is approved for all indications included in the reference product’s (NEUPOGEN®) label
• Approval paves way for greater access to high-quality biologics in the US and
• Underscores Sandoz global leadership in biosimilars
27
Court Denies Motion to Delay Launch of First Approved Biosimilar The first U.S. biosimilar product Zarxio overcame another legal challenge earlier this month when a federal court in California denied a motion to enjoin its commercial launch. The motion was in response to a previous decision in the case, holding that under the patent litigation provisions of the Biologics Price Competition and Innovation Act, the biosimilar applicant was not required to provide its application to the reference product sponsor, a ruling currently on appeal to the Federal Circuit. In a footnote, the judge indicated Zarxio's manufacturer had agreed not to launch the biosimilar product until the earlier of May 11, 2015, or a decision on the pending appeal.
• An “easy/simple” biosimilar target (bio-generic)
• Quality manufacturing site and history of compliance
• Strong Analytical Program
• Strong (extensive?) clinical program
• Timing was right (e.g. ….Neupogen in the news… for MCM-ARS)
• Lots of financial and other backing (??) 28
Paving the pathway into US biosimilars market: Update of USFDA biosimilar guidelines
(and how to potentially duplicate Sandoz's success) So What Did Sandoz do? – It wasn’t easy!
1) Update on USBPCIA regulations
2) Putting BPCIA in context
3) How traditional Generics affect
biosimilars
4) As a business model, is it worth it?
Paving the pathway into US biosimilars market: Update of USFDA biosimilar guidelines
OPPORTUNITY
Forecast for
2020
Historic estimation
for 2011 (in 2007) Today’s sales*
Source: Suzanne M. Sensabaugh. Biological generics: A business case (2007) Journal of Generic Medicines 4 , 186-199, * MAT 03/2012
15
Indications – whether extrapolation is possible and on what these decision are
based. Does the reference have multiple commercially valuable indications? Interchangeability – whether the biosimilar is labeled as interchangeable with
the single previously approved reference biologic – US only. And even then,
does the purchaser need this designation in order to buy the product? Sourcing of reference product for global development of originator and
biosimilar products. Routine for originator products. Progress on sourcing of
reference is being made in EU, US less clear.
Co
mp
ara
tiv
e
Biosimilars will require significant non-clinical and clinical studies**
Post-marketing surveillance and ongoing safety monitoring Proven efficacy with comparable safety profile in: – Patients with CKD and anaemia on haemodialysis (IV) – Patients with CKD and anaemia on haemodialysis (SC) – Patients with CIA (SC) Comparable pharmacokinetics and efficacy
demonstrated in healthy volunteers in two phase I studies In vivo and in vitro assays confirm biosimilarity in terms of pharmacodynamics and antigenicity
Comparability demonstrated with regard to protein structure and product quality
Extensive molecular characterization programme
Risk management plan: 1,500 pts with IV Retacrit 6,700 pts with SC for 3 years (20,000 patient treatment years) 922 renal pts with IV Retacrit
462 renal pts with SC Retacrit 216 oncology pts with SC Retacrit 72 healthy volunteers:
24 in 2 period crossover
48 in 3 period crossover Animal studies
Example: Hospira Biosimilar EPO (Retacrit™) as compared to Originator EPO (Eprex) at each stage
The data required for EC marketing authorization of Hospira’s Biosimilar EPO was GREATER than
the data for the original EPO. And, Hospira is doing extensive studies for U.S. FDA submission.
Post-registration studies Approvalbasedon biosimilarity, safety and effectiveness
Registration studies
Pre-registration studies
Preclinical
4
**Sumant Ramachandra, MD, PhD, MBA
Senior Vice President, Chief Scientific Officer
Hospira
34
Generalized comparison of the data requirements for the development of a standalone biologic [351(a)] as compared to those
expected for a biosimilar/interchangeable biologic [351(k)]. The concept of biosimilarity is fundamentally different from that applied to an originator biologic
where safety, purity, and potency must be established a priori.
“If you don’t know what you have AND
I don’t know what I have, does that mean they are the same?”
Paving the pathway into US biosimilars market: Update of USFDA biosimilar guidelines (and how to potentially duplicate Sandoz's success)
“But considering the many complexities
and the potential massive systemic cost
savings, can anyone blame FDA from
taking its time for further guidance? Rather
be late and right, than early and wrong.”
Using newly acquired lessons learned to realize the goal of
biotechnology filling unmet global public health needs
Thanks Danke Kiitos
Grazie תודה לך
감사합니다
