Biosimilars: The HealthSystem Pharmacy Perspective
Effectively Managing Specialty Therapies: A Forum
for Payers
Steven Lucio, PharmD, BCPS
January 29, 2015
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Key Questions to Be Addressed
• To what extent do hospitals view biosimilars as a viable alternative
for the management of biologic drug costs?
• What are the greatest hurdles to biosimilar adoption?
• How are hospitals preparing for the introduction and subsequent
evaluation of biosimilars?
• What physician education and other clinical strategies are being
employed to elevate interest in biosimilars?
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By 2019….
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Understanding the Biosimilar Paradigm
1. Demystifying the science and comprehending the regulation
2. Reviewing the European market and model
3. Leveraging the Pharmacy and Therapeutics Committee and the
therapeutic interchange infrastructure
4. Learning by example – the “non-biosimilar” biosimilar, tbofilgrastim
5. Monitoring the payer response
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The Principles of Biologic Manufacturing
• As compared to small molecule drugs, all biologics products,
whether originator reference or biosimilar, are:
• More structurally complex
• More difficult to manufacture and demonstrate variability in
their production
• And are more likely to elicit immunogenic responses
• Clinicians, including pharmacists and physicians, do not dwell on
these particular aspects of pharmaceutical manufacturing on a day
to day basis
• Education on these elements is ongoing, but more training is
required
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Biologic Medications Are More Complex Than
Generics
Aspirin
C 9H 8O 4
Filgrastim
C845H1343N233O243S9
Rituximab
C6416H9874N1688O1987S44
www.drugbank.ca, accessed March 20, 2013
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Biologic Manufacturing Is More Complex
www.pharmaceutical-technology.com, accessed Feb.28, 2014
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Biologic Manufacturing Complexity
Mellstedt H, et al. Ann Oncol. 2008;19:411-419.
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Biologic Manufacturing Variability
Nature Biotechnology 2011;29:310-312
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Biologic Manufacturing Changes Are Not
Uncommon (EMA Example)
MabThera
Remicade
Enbrel
Humira
Orencia
RoActemra
Simponi
Cimzia
Rilonacept Regeneron
Ilaris
Benlysta
0
Ann Rheum Dis 2013;72:315-318
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Biologics Can Generate Immune Responses
• Large globular proteins that can
induce a range of immune
responses
• Factors contributing to
immunogenicity:
Product
Erythropoietin
<1
Factor VIII
15-52
Factor IX
1-2
Interferon α
44
• Higher order structure
Interferon β
<5
• Aggregation
IL1 Ra
• Post-translational
modifications
Growth hormone
Infliximab
Nephrol Dial Transplant 2006;21[Suppl 5]:v4-v8, Nat Rev Drug Discov 2012;11:527-540, J Investig Allergol Clin Immunol 2008;18:335-342
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Antibody
formation (%)
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1-2
17-60
What Is a Biosimilar? Is it a Generic Biologic?
• No, because of the complexity, manufacturing variability and
potential for immunogenicity associated with biologics
• A biosimilar is:
• A follow-on biologic that meets extremely high standards
for comparability to an originator biologic drug, and
• Approved via an abbreviated process for use in the same
indications as the originator product with no clinically
meaningful differences in safety, purity, and potency
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Understanding Biosimilar
Legislation
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Biologics Price Competition and Innovation Act
of 2009
• Signed into law on Mar. 23, 2010
• Created the 351(k) or “biosimilar”
pathway
• Granted FDA authority to approve
“highly similar” versions of
previously approved biologics
• “Abbreviated” process
• Biosimilars must demonstrate
safety, purity and potency
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Approval Pathways (Small Molecules)
Product
type
Drug
(Food Drug
and
Cosmetic
Act)
Application
type
New Drug
Application
(NDA)
Abbreviated New
Drug Application
(ANDA)*
*Created by Hatch-Waxman Amendments
Lucio SD, et al. Am J Health-Syst Pharm. 2013;70:2004-2017.
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Application
pathway
Clinical
studies
505(b)1
Yes
Full evaluation of
safety and efficacy
Yes
Studies do not have
to be done by the
application sponsor
No
Approval based upon
bioequivalence
determination
505(b)2
505(j)
Application
requirements
Approval Pathways (Biologics)
Product
type
Biologic
(Public
Health
Service Act)
Application
type
Biologics
License
Application
(BLA)
Biosimilar
Application
(established
2010)
Lucio SD, et al. Am J Health-Syst Pharm. 2013;70:2004-2017.
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Application
pathway
351(a)
351(k)
Clinical
studies
Application
requirements
Yes
Full evaluation of
purity, safety and
potency
Yes
Yes, but abbreviated
process (one clinical
trial)
Interpreting the “Pyramid”
Clinical
Animal Studies
Clinical
Immunogenicity
…the less you
should have to do
here.
Clinical Knowledge
(e.g., Post-Market Experience)
The more work
you do here…
Human Pharmacokinetics
and Pharmacodynamics
Structural and Functional Characterization
Adapted from FDA Webinar: Biosimilar Biological Products
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Interpreting State Legislation Related to
Biologics and Biosimilar Substitution
http://www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx. Accessed Nov. 25, 2014.
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The Regulatory Unknown
• What will biosimilars be named? (e.g. non-proprietary name)
• What will be the requirements for biosimilar interchangeability?
• Will the Food and Drug Administration allow for extrapolation of
indications?
• When will the Food and Drug Administration make these
decisions?
• How will the patent litigation process impact the timing of
product launches?
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Biosimilar Patent Litigation Process
Within 20 days of FDA
accepting a biosimilar
application for review,
access to BLA information
and manufacturing
processes must be provided
to the reference product
sponsor and patent owner.
Sensabaugh SM. Drug Inf J. 2011;45:155-162
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What Can We Learn From Europe?
“A clear understanding of the
scientific principles of the
biosimilar concept
and access to unbiased
information on licensed biosimilars
are important for physicians to
make informed and appropriate
treatment choices for their
patients”
EMA = European Medicines Agency. Weise M, et al. Blood. 2012;120:5111-5117.
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Biosimilars Approved in Europe
Drug Name
Date First
Approved
Suppliers
Somatropin
Apr. 2006
Sandoz Gmb, Biopartners GmbH
Epoetin alfa
Aug. 2007
Hexal AG, MEDICE Pharma GmbH & Co.
KG
Epoetin zeta
Dec. 2007
STADA Arzneimittel AG, Hospira
Filgrastim
Sept. 2008
Ratiopharm GmbH, CT Arneimittel, Teva,
Sandoz, Hexal AG, Hospira
Inflectra (infliximab; Hospira), first biosimilar monoclonal antibody approved
September 10, 2013
JNCCN 2011;9:934-943, IN VIVO Biosimilars Report, October 2010; www.forbes.com, June 28, 2013, Hospira press release, September 10, 2013
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Incentives for Biosimilars in Different
European Countries
Germany
France
Italy
UK
Sweden
High generic
usage
Yes
No
No
Yes
Yes
Quotas
Yes
No
Yes
No
No
Reference
price system
for biosimilars
Yes
No
No
No
No
Nat Rev Drug Discov. 2014;13:99-100
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1st and 2nd Generation Product Shares Epoetin
and Filgrastim Markets in Q4 2011
Therapy
Germany
UK
France
Sweden
Italy
Epoetin (market share by revenue)
Aranesp®
60.8%
70.7%
68.6%
67.6%
41.2%
Eprex®
12.9%
26.0%
26.8%
10.7%
52.0%
Biosimilars
26.3%
3.2%
4.6%
21.7%
6.8%
Filgrastim (market share by revenue)
Neulasta®
73.5%
57.1%
77.0%
58.6%
59.4%
Neupogen®
14.6%
5.1%
11.2%
13.7%
24.9%
Biosimilars
11.9%
37.8%
11.8%
27.7%
15.7%
Nat Rev Drug Discov. 2014;13:99-100
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The Dilemma of Limited Data
• Objective: To compare the efficacy and
safety of erythropoietic stimulating
agents (ESAs), including biosimilars, to
treat anemia in adults with CKC
• All proprietary ESAs prevent blood
transfusions but information on biosimilar
ESAs is less conclusive.
• “In general, data for biosimilar ESA
formulations are sparse and very low
quality, and are not suitable to inform
patients and health providers about the
balance of their benefits and risks”
Cochrane Database Syst Rev 2014 Dec 8;12:CD010590
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Increasing Complexity of Biosimilar Evaluation
Feagan BG, et al. Biologicals. 2014;42:177-183.
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What “Else” Can We Learn From Europe?
• “Biosimilars have been on the
European Market for several
years and have performed as
expected in all licensed
indications, including
extrapolated indications.”
• “In our view, generation of
redundant or merely ‘comforting’
data should not be requested.
Instead extrapolation should be
based on sound and objective
scientific criteria.”
Weise M, et al. Blood. 2014;124:3191-6.
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Use of Biosimilars in Extrapolated Indications
• Consideration of extrapolation across indications must be
scientifically sound, requires:
• Similarity with reference product convincingly demonstrated,
• Relevant mechanism of action and/or receptor are the same
in extrapolated indications,
• Safety profile of biosimilar properly characterized and
acceptable
• May vary by product – filgrastim vs. epoetin vs. infliximab vs.
ritixumab
Weise M, Bielsky MC, De Smet K, et al. Blood. 2012;120:5111-5117; FDA. Guidance for Industry. Scientific considerations in demonstrating biosimilarity to a reference
product, draft guidance, February 2012.
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Health-System Pharmacy
Formulary Management
Strategies
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Important Issues for P & T Committees
• Addition of biosimilars to health system formularies will be a much
more involved process compared to small molecule generics
• Involvement of Pharmacy and Therapeutics Committee
required
• Review will include a more detailed evaluation of safety and
efficacy
• Mechanisms for prescribing, administration and
documentation will be more complex than generic products
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Therapeutic Interchange Application Strategies
• The infrastructure for formulary evaluation and therapeutic interchange
already exists within healthcare organizations
• Existing examples
• Low molecular weight heparins
• Carbapenem antibiotics
• Echinocandin antifungals
• Insulins
• Tacrolimus and other transplant medications
• Topical thrombins
• Tumor necrosis factor – alpha inhibitors
• Erythropoietin stimulating agents
• Somatropin (human growth hormone)
• IVIG
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Elements of a Drug-Evaluation Document
• Brand and generic names
and synonyms
• Use in special populations
• FDA approval information,
including data and FDA
rating,
• Comparisons of the drug’s
efficacy, safety,
convenience and costs
• FDA-approved indications
• Clinical trial analysis and
critique
• Potential non-FDA
approved indications
• Dosage forms and storage
• Recommended dosage
regimens
• Pharmacokinetic
considerations
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• Pregnancy category
• Medication safety
assessment and
recommendations
• Financial analysis,
including
pharmacoeconomic
assessments
Formulary Management: Key Questions
• Will the biosimilar product be
endorsed only for labeled
indications or for off-label
indications as well?
• What is the existing level of
adverse events with the
originator product?
• How will you ensure
appropriate
pharmacovigilance with the
biosimilar?
Lucio SD, et al. Am J Health-Syst Pharm. 2013;70:2004-2017.
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• What was the approval history
of the biosimilar?
• What information is available
concerning the clinical efficacy
and safety of the biosimilar?
• E.g., FDA review document,
published trials, European
data, AMCP dossier, expert
organization guidelines
Formulary Management: Key Questions
(Continued)
• What modifications need to be made to existing order sets and protocols to
include biosimilar products?
• What education will need to be provided to clinicians to prepare for biosimilar
adoption?
• What patient education materials will be needed to support biosimilar use?
• What is the financial value associated with use of a biosimilar?
• Comparative cost and reimbursement
Lucio SD, et al. Am J Health-Syst Pharm. 2013;70:2004-2017.
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Tbo-filgrastim, “The non-biosimilar biosimilar”
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The Tbo-filgrastim Example
Granix® (Teva)
• Approved August 2012 in the US via a biologics license application
(BLA) or 351(a), not the 351(k) biosimilars pathway
• Could not be marketed until
November 2013
• However, approved as a
biosimilar in EU (TevaGrastim)
• Authorized September 15,
2008
• Approved for only one of the indications for which Neupogen
(filgrastim; Amgen) is licensed
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Comparative Properties
Amgen G-CSF
Teva G-CSF
Brand name
Neupogen
Granix
Generic name
Filgrastim
Tbo-filgrastim
BLA
BLA
Ingredient
r-metHuG-CSF
r-metHuG-CSF
Molecular Weight
18,800 daltons
18,800 daltons
175 amino acids
175 amino acids
E. coli
E. Coli
300 mcg, 480 mcg
300 mcg, 480 mcg
Vial and syringe (both PF)
Syringe (PF)
2° to 8°C
2° to 8°C
Application type
Protein length
Expression system
Dosages
Dosage forms
Storage conditions
Neupogen (filgrastim) package insert. Thousand Oaks, CA: Amgen; 2012 May; Tbo-filgrastim package insert. North Wales, PA: Teva Pharmaceuticals USA; 2013 May.
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Comparative Properties
Indications
Neupogen®
Granix®
Cancer patients receiving myelosuppressive
chemotherapy
Yes
Yes
Patients with acute myeloid leukemia receiving
induction or consolidation chemotherapy
Yes
No
Cancer patients receiving bone marrow transplant
Yes
No
Patients undergoing peripheral blood progenitor cell
collection and therapy
Yes
No
Patients with severe chronic neutropenia
Yes
No
C
C
Yes
No
Pregnancy category
Data for use in pediatrics
Neupogen (filgrastim) package insert. Thousand Oaks, CA: Amgen; 2012 May; Tbo-filgrastim package insert. North Wales, PA: Teva Pharmaceuticals USA; 2013 May.
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Tbo-filgrastim Clinical Trial Data
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Mean Absolute Neutrophil Counts (XM02-02)
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Post-Marketing Data with Tbo-filgrastim
• ASCO Annual Meeting 2014 Abstract from Teva
• Review of European Union Periodic Safety Update Reports
• Analyzed safety data from clinical trials and post-marketing sources from
September 15, 2008 to March 31, 2013
• Cumulative exposure to tbo-filgrastim ~ 4,474,929 patient days
• 254 tbo-filgrastim case reports and 461 adverse reactions
• Most commonly occurring terms = allergic type reactions (11), interstitial
pneumonia (4) and splenomegaly (2)
• Conclusions: No new safety risks identified
J Clin Oncol 32,2014 (suppl; abstr e17540)
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Aetna Approval Criteria
Aetna Clinical Policy Bulletin: Hematopoietic Colony-Stimulating Factors (CSFs)
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Anthem Approval Criteria
https://www.anthem.com/provider/noapplication/f0/s0/t0/pw_b157349.pdf?na=pharminfo, accessed June 6, 2014
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Caremark Tbo-filgrastim Coverage
• Cancer patients receiving myelosuppressive chemotherapy
• Patients with acute myeloid leukemia receiving induction or
consolidation chemotherapy
• Cancer patients receiving bone marrow transplant
• Patients undergoing peripheral blood progenitor cell collection and
therapy
• Patients with severe chronic neutropenia
Granix clinical rational, available at : http://www.caremark.com/portal/asset/FEP_Rationale_Granix.pdf; accessed June 6, 2014
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BCBS – Coverage Across Various States
• Illinois
• GRANIX – Tier 4
• Neupogen – Tier 5 (prior authorization)
• Michigan
• GRANIX (preferred brand)
• Montana
• Neupogen (preferred brand)
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Where Do We Stand with
Biosimilar Development?
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Filings Accepted by FDA
• Sandoz – filgrastim (Zarxio)
• Oncologic Drugs Advisory Committee Meeting
(Jan. 7)
• Recommended for approval with all
indications of the reference product
• Possible approval date – March 2015
• Celltrion – infliximab
• Filed for approval; possible approval in summer 2015
• Likely to be substantial patent challenges related to this product
• Apotex – pegfilgrastim
• Announced December 17, 2014
• Possible approval in August 2015
http://www.novartis.com/newsroom/media-releases/en/2014/1835571.shtml;FDA Law Blog, April 2, 2014;
www.hpm.com/pdf/blog/REMICADE%20-%20Celltrion%20DJ%20Complaint.pdf; Celltrion press release, August 11, 2014; The Pink
Sheet Daily, December 19, 2014; www.forbes.com, January 7, 2015.
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Oncologic Drugs Advisory Committee
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM428780.pdf
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Comparison of Clinical Response
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM428780.pdf
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Summary
• Health system pharmacists eagerly await the
introduction of biosimilars
• However, many hurdles to adoption exist
including:
• Lack of familiarity with the nuances of biologic
manufacturing
• Limited understanding of regulatory
requirements and the remaining need for
clarification of outstanding issues
• Competition for attention and resources with
other critical concerns
• Degree of cost savings not defined
• Desire for confirmatory data (i.e. comfort data)
persists
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Biosimilar Opportunities
• Several factors should support a
willingness to consider biosimilars and
help facilitate their adoption
• Need for financial relief for high cost
drugs will not abate
• Desire for alternatives to limited
distribution, originator products given
recent decisions of branded suppliers
• Opportunity to expand influence of
specialty pharmaceuticals
• Existence of formulary management
infrastructure already in place to
support and sustain therapeutic
interchange where clinically
appropriate
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Conclusions
• The biosimilar approval mechanism will offer a process for the
introduction of clinically similar, less-expensive biologics.
• However, biosimilar adoption will be more complex and will require
substantial education of pharmacists, physicians, patients, and many
other stakeholders.
• Health care organizations will need to invest greater resources to
evaluate and use biosimilars.
• The biosimilar market will continue to be influenced by numerous
regulatory decisions, legal rulings and marketing approaches.
• Limited uptake of initial biosimilar opportunities could greatly minimize
the potential for success of subsequent more complex products.
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