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Introduction to Biosimilars
A Clinician’s Perspective
Steven Lucio, PharmD, BCPS
December 9, 2015
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©2014 Novation Confidential.
Question #1: Why Do We Need
Biosimilars?
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©2014 Novation Confidential.
Medication Costs in the US Continue to
Increase! SURPRISE!?!?!!?
• Spending on pharmaceuticals
reached $374 billion, an increase
of 13.1%
• Largest increase since 2001
• Price increases for “protected”
brands increased spending $26.3
billion
• Compared to $11.9 billion
lower spending due to loss
of patent exclusivity
Report available at:
www.imshealth.com/portal/site/imshealth/menuitem.762a961826aad98f53c7
53c71ad8c22a/?vgnextoid=3f140a4331e8c410VgnVCM1000000e2e2ca2R
CRD&vgnextchannel=736de5fda6370410VgnVCM10000076192ca2RCRD&
vgnextfmt=default, accessed, October 31, 2015.
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©2014 Novation Confidential.
• New medicines for hepatitis C,
multiple sclerosis, cancer, and
diabetes drove over $21 billion in
increased spending
How Much Have Drug Prices Increased?
(Oncology Example)
• Letter from 118 physicians of the Mayo
Clinic, calling for lower prices of oncology
drugs
• In the US, the average price of new
cancer drugs increased 5- to 10- fold
over 15 years, to more than $100,000 per
year in 2012.
• The cost of drugs for each additional year
lived (after adjusting for inflation) has
increased from $54,000 in 1995 to
$207,000 in 2013.
• In 2014, all new FDA approved cancers
drugs were priced above $120,000 per
year of use.
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©2014 Novation Confidential.
Mayo Clin Proc. 2015;90:996-1000.
The Value of Generic Drugs
• From 2004 to 2013, generic
drugs have saved the U.S.
health system approximately
$1.5 trillion
• $239 billion saved in 2013
alone
• $140 billion saved in 2013
due to new generic
introductions
• 86% of prescriptions dispensed
in the US are filled with generic
drugs
Report available at
www.gphaonline.org/media/cms/GPhA_
Savings_Report.9.10.14_FINAL.pdf,
accessed October 31, 2015
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©2014 Novation Confidential.
Top Pharmaceutical Sales (2010)
When Small Molecule Drugs Dominated Drug Spend
Drug
US Sales (millions)
1
SM
Clopidogrel (Plavix®)
$6,154
2
SM
Atorvastatin (Lipitor®)
$5,329
3
SM
Fluticasone/ salmeterol inhaler (Advair®)
$4,026
4
SM
Aripiprazole (Abilify®)
$3,606
5
SM
Pioglitazone (Actos®)
$3,582
6
B
Etanercept (Enbrel®)
$3,304
7
SM
Montelukast (Singulair®)
$3,219
8
SM
Quetiapine (Seroquel®)
$3,107
9
B
Infliximab (Remicade®)
$3,099
10
B
Bevacizumab (Avastin®)
$3,068
SM = small molecule drug, B = biologic drug
EvaluatePharma. Available at
info.evaluategroup.com/rs/evaluatepharmaltd/images/SV2014.pdf. Accessed July 2015.
Top Pharmaceutical Sales (2014)
Biologics Now Represent More Top Spend Pharmaceuticals
Drug
US Sales (millions)
1
SM
Sofosbuvir (Sovaldi®)
$10,098
2
B
Adalimumab (Humira®)
$6,078
3
SM
Glargine insulin (Lantus®)
$5,759
4
B
Etanercept (Enbrel®)
$4,311
5
B
Infliximab (Remicade®)
$4,154
6
SM
Aripiprazole (Abilify®)
$3,886
7
B
Rituximab (Rituxan®)
$3,707
8
B
Pegfilgrastim (Neulasta®)
$3,523
9
SM
Fluticasone/ salmeterol (Advair®)
$3,325
10
B
Bevacizumab (Avastin®)
$2,928
SM = small molecule drug, B = biologic drug
EvaluatePharma. Available at
info.evaluategroup.com/rs/evaluatepharmaltd/images/SV2014.pdf. Accessed July 2015.
Question #2: When can we
Expect the First Generic
Biologic Drug?
Answer: It’s complicated!
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©2014 Novation Confidential.
While Many Biologic Drugs Are Nearing The
End of Their Exclusivities
Global Sales 2013, US$ Billion
9.1
Adalimumab (Humira)
Etanercept (Enbrel)
Infliximab (Remicade)
Insulin Glargine (Lantus)
Rituximab (Mabthera)
Bevacizumab (Avastin)
Interferon Beta-1A (Avonex,…
Trastuzumab (Herceptin)
Glatiramer Acetate (Copaxone)
Ranibizumab (Lucentis)
Pegfilgrastim (Neulasta)
7.7
7.5
7.1
6.2
5.6
5.4
5.1
4.7
4.2
4.2
EU Expiry
Date
US Expiry
Date
2018
2016
2015
2028
2015
2018
Expired
Expired
Expired
2016
2019
2017
Expired
Expired
Expired
2019
2015
Expired
2016
2016
2015
Expired
0 1 2 3 4 5 6 7 8 9 10
Adapted from IMS Health. http://www.imshealth.com/deployedfiles/imshealth/Global/Content/Healthcare/
Life%20Sciences%20Solutions/Generics/IMSH_Biosimilars_WP.pdf. Accessed June 2015.
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©2014 Novation Confidential.
Biologic Drugs are Much More Complex
Molecules
Aspirin
N Engl J Med 2011;365:385-388.
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©2014 Novation Confidential.
Monoclonal antibody biologic
Biologics Are More Difficult to Manufacture
(and Subject to Variability)
Small molecule drugs
Biologic medications
• Well understood organic medicinal
chemistry reactions
• Very complex manufacturing steps
that require various stages of
purification, production, and
validation
• Since the product is less
complicated, easier to ensure
structure is not altered due to
manufacturing changes
• Given simplicity of the
molecules, it is possible to
create a “generic” or
bioequivalent version.
• Rely on living organisms
• Any modification can alter the final
structure and function of the protein
• Due to the size, complexity, and
inherent variability of biologics,
can only create “highly similar”
or “biosimilar” version of
originator molecule.
NCCN biosimilars white paper, J Natl Compr Canc Netw. 2011;9(suppl 4):S1-S22.
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©2014 Novation Confidential.
Due to Differences in Small Molecules and
Biologics, Different Legislation Was Needed
Hatch-Waxman, 1984
Biosimilars Act, 2010
http://www.gpo.gov/fdsys/pkg/STATUTE-98/pdf/STATUTE-98-Pg1585.pdf;
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM216146.pdf
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©2014 Novation Confidential.
Question #3: How easy will it
be to adopt and use
biosimilars?
Answer: That’s a great question!
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©2014 Novation Confidential.
Differentiating Generics and Biosimilars
Key Attributes
Generics
Biosimilars
Approval
No clinical trials required
Must conduct at least one
trial
Indications (Uses)
Same as originator
May not include all
indications
Same generic name
Yes
Probably not
Interchangeable
Yes, upon approval
Possible, but not granted
immediately
Cost to develop
$1 to $4 million
$100 to $250 million
Price discounts
50% to 90%
15% to 30%
Formulary Review Required
No
Yes
Role of the Branded
Company
Limited or non-existent
Prominent
Lucio SD, Stevenson JG, Hoffman JM. Biosimilars: implications for health-system pharmacists. Am J Health Syst Pharm.
2013;70(22):2004-2017.
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©2014 Novation Confidential.
The Mystery of Interchangeability
Biosimilar Interchangeability (per FDA) Means
• The interchangeable biosimilar can be expected to produce the same clinical
result in any given patient,
• Can be substituted without the intervention of the health care provider (states
may have different ideas)
• For a biological administered more than once to a patient, the is no greater
risk of switching or alternating between products (biosimilar and originator),
than using the originator without switching
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/Thera
peuticBiologicApplications/Biosimilars/ucm241719.htm
The Mystery of Interchangeability
What Do We Mean By Generic Interchangeability
• Generic drug – A drug that is identical – or bioequivalent – to a brand name
drug in dosage form, safety, strength, route of administration, quality,
performance characteristics and intended use.
• “Therapeutic equivalence” code (ie. “A” rating)
• Metformin, simvastatin, linezolid, vancomycin
Understanding Generic Drugs, www.fda.gov
The Mystery of Interchangeability
Can all Generic Drugs be Substituted?
• Critical dose drugs – Drugs in which comparatively small differences in dose
or concentration may lead to serious therapeutic failures and/or serious drug
reactions
• Examples
• Coumadin vs. warfarin
• Prograf vs. tacrolimus
• Anti-seizure medications
ACCF/AHA 2011 Health Policy Statement on Therapeutic Interchange and Substitution, available at:
http://circ.ahajournals.org/content/124/11/1290.extract
Examples of Therapeutic Interchange Of
Distinct Molecules
Non-acute setting
Acute care/Hospital setting
• Diabetes
• Topic agents to prevent of slow
bleeding (i.e. thrombins)
• Insulins
• Inhalers
• Asthma
• COPD
• Cholesterol
• Statins
• PCSK9 inhibitors?
• Human growth hormone
• Intravenous immune globulins
• Injectable and oral
anticoagulants
• Antifungals
• Echinocandins
• Lipid amphotericin B
• Injectable antibiotics
Where do biosimilars fit on the continuum of interchangeability and
substitution?
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©2014 Novation Confidential.
How Much Progress Have We Made in the Last
Five Years?
• One official biosimilar approved
• Filgrastim-sndz (Zarxio; Sandoz), competing version of branded product
Neupogen (filgrastim; Amgen)
• Six other biosimilar applications pending before the Food and Drug
Administration; one application received complete response letter
• Many unknowns remain
• When will additional biosimilars be approved?
• Will more complex biosimilars be approved for all of the uses of the
branded biologic?
• What will biosimilars be called? (naming)
• What information is required to deem a biosimilar interchangeable?
• How will FDA’s decision align with actions of state legislatures?
• How will biosimilars be labeled?
Novartis (press release), September 3, 2015; The Pink Sheet, Pending Biosimilar FDA Performance Tracker, accessed
December 1, 2015.; http://www.fiercebiotech.com/story/novartis-comes-enbrel-latest-biosimilar-shot-amgen/2015-10-02
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©2014 Novation Confidential.
Challenges for Physicians and Others
• Lack of familiarity with the biosimilar paradigm and the processes for biologic
manufacturing and approval
• Differences between small molecule drugs and biologics
• Inherent variability of all biologics (branded and biosimilar)
• Understanding of the biosimilar approval pathway
• Appropriate extrapolation of indications
• Absence of final definition for critical biosimilar attributes
• In the absence of definition, many organizations attempting to define the
narrative of biosimilars
• Acceptance of the biosimilar paradigm includes a willingness to trust more in
analytical evaluation rather than relying solely on clinical studies
• Many aspects of the financial attributes of biosimilars (costs and
reimbursements) remain to be defined
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©2014 Novation Confidential.
Challenge (Sorting Through the Messages)
• Branded Companies
• Genentech
• Hospira
• AbbVie
• Teva
• Janssen Biotech
• Sandoz
• Pfizer
• Apotex
• Amgen
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• Generic Companies
©2014 Novation Confidential.
Biosimilar Companies?
• Teva
• Sandoz
• Amgen
• Pfizer
• Baxalta
• Celltion
The “Biosimilar” 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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©2014 Novation Confidential.
Biosimilars Balancing Act
How do clinicians become comfortable relying on analytical data to greater
extent?
Clinical
Analytical
Summary
• The biosimilar pathway continues to progress, even though at a less than
desirable pace.
• The increasing costs of pharmaceuticals necessitate that a concerted and
continued effort be made to support biosimilar introduction and use in order to
create competition and lower comparative expense for similar biologic drugs.
• Health care organizations and providers will have to invest greater resources
to biosimilar evaluation prior to use than what currently occurs with generic
drugs.
• Regulatory, legal, financial, and clinical practice factors will all influence the
extent to which biosimilars are truly viable in the US.
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©2014 Novation Confidential.