11/16/2015 1 STEVEN D. LUCIO, PHARMD, BCPS SENIOR DIRECTOR OF CLINICAL SOLUTIONS AND PHARMACY PROGRAM DEVELOPMENT NOVATION, LLC Biologics and Biosimilars: Preparing for the Future LEARNING OBJECTIVES 1. Define “biosimilar” based current FDA guidance and describe similarities and differences between biosimilar and originator biologic agents 2. Review key aspects of the comparability exercise for approval of biosimilars per current FDA guidance 3. Evaluate experience with biosimilars in the EU 4. Describe current and emerging biosimilars in the US Learning Objectives Top Pharmaceutical Sales (2014 vs 2010) 2014 2010 Drug Manufacturer US Sales (millions) Drug Manufacturer US Sales (millions) 1 SM Sofosbuvir (Sovaldi®) Gilead $10,098 1 SM Clopidogrel (Plavix®) BMS $6,154 2 B Adalimumab (Humira®) AbbVie $6,078 2 SM Atorvastatin (Lipitor®) Pfizer $5,329 3 SM Glargine insulin (Lantus®) Sanofi $5,759 3 SM Fluticasone/ salmeterol inhaler (Advair®) GSK $4,026 4 B Etanercept (Enbrel®) Amgen $4,311 4 SM Aripiprazole (Abilify®) Otsuka $3,606 5 B Infliximab (Remicade®) J&J $4,154 5 SM Pioglitazone (Actos®) Takeda $3,582 6 SM Aripiprazole (Abilify®) Otsuka $3,886 6 B Etanercept (Enbrel®) Amgen $3,304 7 B Rituximab (Rituxan®) Roche $3,707 7 SM Montelukast (Singulair®) Merck $3,219 8 B Pegfilgrastim (Neulasta®) Amgen $3,523 8 SM Quetiapine (Seroquel®) AstraZeneca $3,107 9 SM Fluticasone/ salmeterol (Advair®) GSK $3,325 9 B Infliximab (Remicade®) J&J $3,099 10 B Bevacizumab (Avastin®) Roche $2,928 10 B Bevacizumab (Avastin®) Roche $3,068 SM = small molecule drug, B = biologic drug EvaluatePharma. Available at info.evaluategroup.com/rs/evaluatepharmaltd/images/SV2014.pdf. Accessed July 2015.
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11/16/2015
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STEVEN D. LUCIO, PHARMD, BCPSSENIOR DIRECTOR OF CLINICAL SOLUTIONS AND
PHARMACY PROGRAM DEVELOPMENTNOVATION, LLC
Biologics and Biosimilars: Preparing for the Future
LEARNING OBJECTIVES
1. Define “biosimilar” based current FDA guidance and describe similarities and differences between biosimilar and originator biologic agents
2. Review key aspects of the comparability exercise for approval of biosimilarsper current FDA guidance
3. Evaluate experience with biosimilars in the EU
4. Describe current and emerging biosimilars in the US
Learning Objectives
Top Pharmaceutical Sales (2014 vs 2010)
2014 2010
Drug ManufacturerUS Sales (millions)
Drug ManufacturerUS Sales (millions)
1 SMSofosbuvir (Sovaldi®)
Gilead $10,098 1 SMClopidogrel (Plavix®)
BMS $6,154
2 BAdalimumab (Humira®)
AbbVie $6,078 2 SMAtorvastatin (Lipitor®)
Pfizer $5,329
3 SMGlargine insulin (Lantus®)
Sanofi $5,759 3 SM
Fluticasone/ salmeterol inhaler (Advair®)
GSK $4,026
4 BEtanercept (Enbrel®)
Amgen $4,311 4 SM Aripiprazole (Abilify®)
Otsuka $3,606
5 BInfliximab (Remicade®)
J & J $4,154 5 SM Pioglitazone (Actos®)
Takeda $3,582
6 SMAripiprazole (Abilify®)
Otsuka $3,886 6 B Etanercept(Enbrel®)
Amgen $3,304
7 BRituximab (Rituxan®)
Roche $3,707 7 SM Montelukast(Singulair®)
Merck $3,219
8 BPegfilgrastim (Neulasta®)
Amgen $3,523 8 SMQuetiapine (Seroquel®)
AstraZeneca $3,107
9 SMFluticasone/ salmeterol (Advair®)
GSK $3,325 9 B Infliximab (Remicade®)
J & J $3,099
10 BBevacizumab(Avastin®)
Roche $2,928 10 BBevacizumab (Avastin®)
Roche $3,068
SM = small molecule drug, B = biologic drug
EvaluatePharma. Available at info.evaluategroup.com/rs/evaluatepharmaltd/images/SV2014.pdf. Accessed July 2015.
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Globally, Biologics Share of Total Prescription Medicine Sales is Increasing
11%
15%
18%
19‐20%
0
5
10
15
20
25
2002 2007 2012 2017
Biologics Share of T
otal S
ales (%
)
IMS Health. http://www.imshealth.com. Accessed June 2015.
Projected
The Patent Cliff and Growth Potential for the Biosimilars Market
Adapted from IMS Health. http://www.imshealth.com/deployedfiles/imshealth/Global/Content/Healthcare/Life%20Sciences%20Solutions/Generics/IMSH_Biosimilars_WP.pdf. Accessed June 2015.
9.1
7.7
7.5
7.1
6.2
5.6
5.4
5.1
4.7
4.2
4.2
0 1 2 3 4 5 6 7 8 9 10
Adalimumab (Humira)
Etanercept (Enbrel)
Infliximab (Remicade)
Insulin Glargine (Lantus)
Rituximab (Mabthera)
Bevacizumab (Avastin)
Interferon Beta‐1A (Avonex, Rebif)
Trastuzumab (Herceptin)
Glatiramer Acetate (Copaxone)
Ranibizumab (Lucentis)
Pegfilgrastim (Neulasta)
Global Sales 2013, US$ BillionEU Expiry
DateUS Expiry
Date
2018 2016
2015 2028
2015 2018
Expired Expired
Expired 2016
2019 2017
Expired Expired
Expired 2019
2015 Expired
2016 2016
2015 Expired
Biosimilars are Projected to Moderate Drug Expenditures and Expand Patient Access to Biologics
• Continuing growth in US prescription drugs1
– Top drugs for 1st 9 months of 2014 based on expenditures
In clinics: infliximab, pegfilgrastim, epoetin alfa
In hospitals: infliximab, rituximab, pegfilgrastim
– 7–9% projected increases in total drug expenditures for 2015 across all settings
• Biosimilars are predicted to lead to a $44.2 billion reduction(range $13‐$66 billion) in direct spending on biologic drugs from 2014‐20242
1. SchumockGT, et al. Am J Health‐Syst Pharm. 2015;72:e19‐38.2. MulcahyAW, et al. http://www.rand.org/content/dam/rand/pubs/perspectives/PE100/PE127/
RAND_PE127.pdf. Accessed June 2015.
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Small Molecule Drugs vs. Biologics
Mellstedt H. EJC Supplements. 2013;11:1‐11.
Unlike Producing Small Molecule Drugs, the Manufacturing Process for Biologics is Complex
Mellstedt H, et al. Ann Oncol. 2008;19:411‐419.
Cloning into DNA VectorTransfer into Host Cell
ExpressionScreening / Selection
Cell Productionin Bioreactors
Purification Through
Chromatography
CellExpansion
Recovery ThroughFiltration or
Centrifugation Characterizationand Stability
PurifiedBulk Drug
Originator Manufacturing Process Changes
• Small modifications may result in gradual changes
• Despite these differences, when the products are within a prespecified acceptable range, the products are marketed with no change in label
• If large alterations occur, analytical studies (and possibly additional clinical studies) are required to compare post‐change product with existing pre‐change product
Biosimilars are NOT Generics of Existing Biologics
• Traditional generic drugs are exact copies of existing drugs
• However, biosimilars are much bigger than a typical genericcopy of a small molecule
• Biologics are also made up of amino acids, which form uniquefolds and glycosylation patterns may also vary
• Therefore, they are muchmore complex
• Combined with the complicated manufacturing process, anexact copy of a biologic cannot be made
Weise M, et al. Blood. 2012;120:5111‐5117.
• Signed into law on March 23, 2010
• Created the 351(k) or “biosimilar” pathway granting FDA authority to approve “highly similar” versions of previously approved reference biologics
• Intended to be an “abbreviated” process
• Biosimilar applicants must be able to ensure safety, purity and potency of their products
Biologics Price Competition and Innovation Act of 2009
FDA. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM216146.pdf. Accessed July 2015.
Definitions
Per the FDA, Biosimilar or Biosimilarity means:
• That the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and
• There are no clinically meaningful differencesbetween the biological product and the reference product in terms of the safety, purity, and potency of the product
FDA. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm. Accessed June 2015.
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FDA Specifications for Biosimilars vs. Reference Biologic
Biosimilar ProductSpecification
Comparisonwith Reference
Formulation May be different
Delivery device/container May be different
Routes of administrationMay obtain licensure for fewer than all routes of administration for which reference product is licensed
Conditions of useMay obtain licensure for fewer than all conditions of use for which reference product is licensed
Description First‐tomarket biologic molecule; will likely be the reference product
“Highly similar” to reference product; approved via biosimilarspathway
A biosimilar deemedthat can be substituted for the reference without permission from prescriber
It is “another brand name” of an already approved biologic
Biologic that has been altered to achieveimproved clinical outcomes
Depth of data submitted to the FDA
“Standard” data package: efficacy and safety
Abbreviateddata package for comparability
Abbreviated data package for comparability; more information on efficacy and safety
“Standard” datapackage: efficacy and safety
“Standard” datapackage: efficacy and safety
Compared to originator?
N/A Yes Yes Yes or no Likely (standard of care)
Implications Biosimilar pricing; explicit regulatoryoversight on comparison with reference; possible pharmacist substitution (for interchangeable); potential for indication extrapolation
Different pricingstructure; substitution issues; cannot extrapolate indications
New entity
Adapted from: Lucio et al. Am J Health Syst Pharm. 2013;70(22):2004‐2017.
Biologics: A Regulatory Perspective (G‐CSF Example)
351(a)Originator
351(k)Biosimilar
351(k)Interchangeable Biosimilar
351(a)Non‐originator Biologic
351(a)Next‐generation “Bio‐better”
BiologicFilgrastim(Neupogen)
Filgrastim‐sndz(Zarxio)
None yet approvedTbo‐filgrastim(Granix)
Pegfilgrastim(Neulasta)
Original Date of Approval
February 20,1991
March 6, 2015 N/A August 29, 2012 January 31, 2002
www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name. Accessed July 2015.
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Demonstrating Biosimilarity:General Principles
• The clinical efficacy and safety of the biologic molecule has already been demonstrated (ie, by the innovator)
• The biosimilar sponsor only requires evidence that the candidate biosimilar is not significantly different from the reference product
– Goal is not to replicate unnecessary clinical trials
– Smaller‐scale direct comparisons and extrapolation
• When a biosimilar is approved, there should not be an expectation that there will be differences in safety and efficacy
FDA. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm. Accessed June 2015.
Biosimilar Evaluation–Step‐wise Totality of Evidence Approach
Analytical Studies are the Foundation for Biosimilar Development
• If extensive structural and functional comparability assessment does not reveal significant differences between a biosimilar and reference biologic, it is highly unlikely that trials in patients would uncover any difference in safety and efficacy
De Mora F. Br J Clin Pharmacol. 2015 Apr 11. [Epub ahead of print]Weise M, et al. Blood. 2014;124:3191‐3196.
• Clinical study(ies) should be designed to establish statistical evidence that the proposed product is neither inferior to the reference product by more than a specified margin nor superior to the reference product by more than a specified margin
Li EC, et al. Drug DiscovToday. 2015;20(S2):1‐9.http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ ucm290967.htm
Endpoints and study populations are selected that will be clinically relevant and sensitive in detecting clinically meaningful differences
Extrapolation of Indications
Extrapolation of data from a clinical trial of a biosimilar conducted in one disease to support approval for additional indications for which the reference product is already licensed
• Factors to be considered:
– Clinical experience with the reference product
– Mechanism(s) of action in each indication
– Target receptors
– Product structure and target/receptor interactions
– PK and biodistribution in different patient populations
– Differences in the safety/immunogenicity profile between indications
Weise M, et al. Blood. 2014;124:3191‐3196.http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm
Per the FDA, Interchangeable or Interchangeabilitymeans:
• The biological product is biosimilar to the reference product
• It can be expected to produce the same clinical result as the reference product in any given patient
• For a product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and its reference product is not greater than the risk of using the reference product without such alteration or switch
• Interchangeable is an FDA designation– Requires higher standards than ‘biosimilarity’ alone
• A product with an interchangeable designation may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product
• HOWEVER– FDA approval requirements for interchangeable designation and trial
design for testing are not finalized
– State substitution laws will impact practice
– Any biological product under consideration for substitution must first be approved as "interchangeable" by the FDA
http://www.who.int/medicines/services/inn/bq_innproposal201407.pdf. Accessed June 2015. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name. Accessed June 2015.
• All biologics receive a distinct, four letter suffix
• Suffix must be devoid of meaning
• Proposed effect on G‐CSFs
• Filgrastim = Filgrastim‐jcwp
• Filgrastim‐sndz = Filgrastim‐bflm
• Tbo‐filgrastim = Filgrastim‐vkzt
• Peg‐filgrastim= pegfilgrastim‐ljfd
European Biosimilars Experience
Active Substance Products Approval
Epoetin alfaAbseamedBinocrit
Epoetin Alfa Hexal
8/20078/20078/2007
Epoetin zetaRetacritSilapo
12/200712/2007
Filgrastim
AccofilBiograstim
Filgrastim HexalGrastofilNivestim
RatiograstimTevagrastim
Zarzio
9/20149/20082/200910/20136/20109/20089/20082/2009
Folitropin alfaBemfolaOvaleap
3/20149/2013
InfliximabInflectraRemsima
9/20139/2013
Insulin glargine Abasaglar/Abasria 9/2014
Somatropin Omnitrope4/2006
http://www.ema.europa.eu. Accessed June 2015.
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Biosimilars Market Uptake in Europe
Assessing biosimilar uptake and competition in European markets 2014. www.imshealth.com/. Accessed June 2015.
Percent of T
reatm
ent Days, 2013
Experience with Biosimilars in the EU
• Safety and efficacy of approved and marketed biosimilars has been consistent with experience with the reference biologics, with no specific safety issues identified
Mikhail A, Farouk M. AdvTher. 2013;30:28‐40.Gascon P, et al. Support Care Cancer. 2013;21:2925‐2932.Chamberlain PD. Biosimilars. 2014;4:23‐43.http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_report_en.pdf. Accessed Jan 2015.
Bloomberg Business, April 22, 2015; FiercePharma, July 6, 2015
Financial Impact of Biosimilars in Europe
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Non‐originator (“me‐too”) Biologics ≠ Biosimilars
Regulatory Requirements Vary in Different Parts of the World
Examples:• Reditux (rituximab): India• Kikuzubam (rituximab): Mexico• Yi Sai Pu (etanercept): China• Etanar (etanercept): China• Genfaxon (interferon beta): Russia
Scheinberg M, Kay J. Nat Rev Rheumatol. 2012;8:430‐436.http://gabionline.net/Reports/Biosimilars‐in‐emerging‐markets. Accessed June 2015.
Biosimilars in the US
Drug INN ManufactureraBLA
submittedFDA
approval
Zarxio™ filgrastim‐sndz Sandoz 7/2014 3/2015
Remsima infliximab Celltrion Inc. 8/2014 ?
pegfilgrastim Apotex Inc. 12/2014 ?
Retacrit™ epoetin zeta Hospira 1/2015 Completeresponse letter
Grastofil™ filgrastim Apotex Inc. 2/2015 ?
Etanercept Sandoz 10/2015 ?
The Pink Sheet, FDA Performance Tracker, Biosimilars, accessed 11/15/2015
Ongoing litigation will determine the exact date of biosimilar launch!
Dosage forms Vial and syringe (both PF) Syringe (PF)
Storage conditions 2° to 8°C 2° to 8°C
Drugs@FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103353s5184lbl.pdf. Accessed June 2015.Drugs@FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125553lbl.pdf. Accessed June 2015.
Approved for 5 of the 6 indications of the originator product
Biosimilar Filgrastim Clinical Studies
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM428780.pdfhttp://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM428782.pdfLi EC, et al. Drug Discov Today. 2015;20(S2):1‐9.
• Comparative pivotal studies (US‐licensed Neupogen as the reference product )
– PK/PD study (EP06‐109) in healthy volunteers
– Comparative safety and efficacy study (EP06‐302) in breast cancer patients
• Supportive data
– 4 PK/PD studies in healthy volunteers
– 1 Single‐arm safety and efficacy study in breast cancer patients
– Data from healthy stem cell donors (performed as part of the European submission package as well as post marketing approval in Europe)
• “The results of the clinical development program suggest that the Applicant’s data meets the requirement for a demonstration of ‘no clinically meaningful differences’ between the proposed product and the reference product in terms of safety, purity, and potency”
• “FDA’s analysis of the efficacy and safety results of EP06‐302 focused on Cycle 1 and these data provided additional support that there are no clinically meaningful differences between EP2006 and US‐licensed Neupogen.”
From the FDA Briefing Document, Oncologic Drugs Advisory Committee Meeting. January 7, 2015.
• FDA Purple Book: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations
• FDA Briefing Documents
• European Medicines Agency Scientific Guidelines on Biosimilar Medicines
• European Public Assessment Reports (materials for each biosimilar approved by the EMA)
• Peer‐reviewed literature
• Generics and Biosimilars Initiative
• Biosimilars Forum
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Practice Considerations for Biosimilars
• Which biosimilar agents are relevant to your practice?
• What is the timing for the introduction of these biosimilars?
• What factors will be important for incorporation of biosimilars into your clinical practice?
– Is there a formulary review process?
– Reimbursement issues
– Documentation, record‐keeping
• Pharmacovigilence
• Biosimilars education
– Multidisciplinary teams
– Patients
Summary
• Biologics are complex drugs that cannot be made “generic”
• A biosimilar is a biologic demonstrated to be highly similar to a reference product through appropriate comparative, head to head quality, non‐clinical and clinical studies
• Analytical studies of structure and function form the basis for the development of a biosimilar
• The comparability exercise used to demonstrate that a biosimilar is “highly similar” to a reference biologic is scientific, robust, and regulated
• Biosimilar uptake continues to increase in Europe, and no specific safety issues have been identified for approved and marketed biosimilars
• The first biosimilar is now approved in the US, with more under FDA review
• Incorporation of biosimilars into US clinical practice offers opportunity for health care cost savings and increased patient access to biologic therapies