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New Drug Updates:Biosimilars
Christopher Allen, PharmD, BCOP
Supervising Pharmacist, Infusion Therapy
UAB Hospital
September 30, 2016
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Objectives
Describe current information concerning approval of biosimilar projects List currently available biosimilar products Examine factors that should be considered for a
biosimilar's inclusion into your institution's medication-use process Identify potential differences in available
biosimilars and reference products that may affect the medication use process (technicians)
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Disclosure Statement
Christopher Allen reports that he has no financial relationships with any commercial supporters or providers
Products not yet approved by the Food & Drug Administration may be discussed during this presentation.
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Drug Expenditures in 2015
In 2015, biological products represented (in terms of overall expenditures)…
Eight of the top 25 drugs overall (~$40 billion) – 7 with + growth
Nineteen of the top 25 drugs in clinics, including the top 9 (~$26.5 billion) – 17 with + growth
Fifteen of the top 25 drugs in nonfederal hospitals, including the top 6 (~$8.7 billion) – 11 with + growth
Antineoplastic agents and biologicals rank #1 and #5, respectively, by expenditures in nonfederal hospitals
Projected increases of ~12%, ~16%, and ~11%, respectively
http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/ucm113522.htm. July 7, 2016 (accessed August 13, 2016).
Schumock GT, et al. Am J Health Syst Pharm. 2016; 73(14): 1058-75.
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How did we get to this point?
1984
Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Act)
2010
Biologics Price Competition and Innovation (BPCI) Act
351(k) Biosimilar application
Lucio, SD, et al. Am J Health Syst Pharm. 2013; 70(15): 2004-2017.
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Potential Growth in Biosimilars?
U.S. Patent Expiration DateAdalimumab (Humira®) December 2016Etanercept (Enbrel®) 2012/2028Infliximab (Remicade®) 2018Pegfilgrastim (Neulasta®) ExpiredInterferon beta-1a (Avonex® / Rebif®) ExpiredRituximab (Rituxan®) September 2016Bevacizumab (Avastin®) 2019Epoetin alfa (Epogen® / Procrit®) ExpiredTrastuzumab (Herceptin®) 2019
http://www.gabionline.net/Biosimilars/Research/US-54-billion-worth-of-biosimilar-patents-expiring-before-2020. September 30, 2011 (accessed August 13, 2016).
http://www.gabionline.net/Generics/General/The-biggest-drug-patent-losses-for-2013. May 17, 2013 (accessed August 13, 2016).
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Regulatory Definition of a Biosimilar
Food and Drug Administration (U.S)
A biological product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components and for which there are no clinically meaningful differences in terms of safety, purity and potency
http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. April 2015 (accessed August 13, 2016).
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM216146.pdf. (accessed August 13, 2016).
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Biosimilar Manufacturing –An Impossible Copycat Process
Mellstedt, H, et al. Ann Oncol. 2008; 19(3): 411-9.Lucio, SD, et al. Am J Health Syst Pharm. 2013; 70(15): 2004-2017.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073476.pdf. June 2005 (accessed August 25, 2016).
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FDA Guidelines for Demonstrating Biosimilarity – A Stepwise Approach
Comparative process, not a demonstration of therapeutic equivalence!
Structure Function Animal ToxicityHuman Pharmacokinetics / PharmacodynamicsClinical ImmunogenicityClinical Safety and Effectiveness
The FDA reserves the right to determine if more data is needed (or less in some cases!)
Totality-of-the-evidence approach
http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. April 2015 (accessed August 13, 2016).
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Totality of the Evidence – What’s the Difference?
http://www.clevelandclinicmeded.com/online/monograph/biologicsvi-optimizing-therapies/biosimilars.htm. Accessed August 30, 2016.
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FDA Biosimilar Specifications
Biosimilar Product Specification Comparison with Reference ProductFormulation May be differentDelivery device/container May be differentRoutes of administration May obtain licensure for fewer than all
routes of administration for which reference product is licensed
Indications May obtain licensure for fewer than all indications for which reference product is licensed
Strength Must be the same
http://www.fda.gov/downloads/Drug/GuidanceComplianceRegulatory/Information/Guidances/UCM444661.pdf. April 2015 (accessed August 13, 2016).
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Naming of a Biosimilar
WHO & FDA
Biosimilar identified by international nonproprietary name (INN) + four letter suffix
EMA
Biosimilar & reference product share INN
JMCP 2016
Pharmacists prefer INN + suffix for biosimilars, but would be more confident in substituting interchangeable products if INN shared
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM459987.pdf. August 2015 (accessed August 25, 2016).
http://www.who.int/medicines/services/inn/WHO_INN_BQ_proposal_2015.pdf?ua=1. October 2015 (accessed August 25, 2016)http://www.gabionline.net/Biosimilars/General/EU-majority-says-same-INNs-for-biosimilars. February 28, 2014 (accessed August
25, 2016).Tomaszewski D. J Manag Care Spec Pharm. 2016: 22(8): 919-26.
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Audience Response Question #1
Which of the following details MUST be identical when comparing a biosimilar product to its reference product?
a. Labeled indications
b. Routes of administration
c. Strength
d. Formulation
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THE CURRENT BIOSIMILAR PRODUCT LANDSCAPE
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Filgrastim-sndz (Zarxio®)
FDA approval: March 6, 2015
“Key” differences:
Approved for 5 of the 6 indications that Neupogen®
carries
Not labeled to increase survival in patients acutely exposed to myelosuppressive doses of radiation
Available only as prefilled syringes
Filgrastim-sndz (Zarxio®) [package insert]. Princeton, NJ: Sandoz, Inc.; 2016.Filgrastim (Neupogen®) [package insert]. Thousand Oaks, CA: Amgen, Inc.; 2016.
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125553Orig1s000SumR.pdf. March 6, 2015 (accessed August 13, 2016).
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Filgrastim-sndz (Zarxio®) – Approval Data
Supported by evaluations of analytical similarity and animal studies of pharmacodynamics and toxicity
Preclinical study - Sörgel F, et al.
Compared biosimilar filgrastim, U.S. reference product, and E.U. reference product
Protein structure and bioactivity “highly similar”
Pharmacokinetic and pharmacodynamics parameters bioequivalent
No observed differences in safety or immunogencity
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125553Orig1s000SumR.pdf. March 6, 2015 (accessed August 13, 2016).
Sörgel, F, et al. BioDrugs. 2015; 29(2): 123-31.
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Filgrastim-sndz (Zarxio®) – Approval Data
Clinical study – Blackwell K, et al.
Conducted in 218 women with breast cancer receiving TAC x 6 cycles (docetaxel, doxorubicin, cyclophosphamide)
Randomized 1:1:1:1
Biosimilar, Reference, Biosimilar-Reference or Reference-Biosimilar (alternating with each cycle)
Hospitalization due to febrile neutropenia, incidence of infections, depth of/time to ANC nadir, and time to ANC recover equivalent; higher number of patients with FN with biosimilar (but within expected variability)
No observed differences in safety profile
Blackwell, K, et al. Ann Oncol. 2015; 26(9): 1948-53..
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Filgrastim Biosimilars –The European Experience
Currently, there are 8 branded biosimilar filgrastim products approved for use in the European Union
2010 EORTC Guidelines for the Use of G-CSF
Filgrastim biosimilars are an acceptable treatment option (Grade A recommendation)
Recommends that clinicians identify products by brand name to ensure there are no changes in treatment without informing the physician and patient
Pooled data from 5 post-approval studies of Zarxio®
Among 1,302 patient, rates of febrile neutropenia (2.2%) and severe neutropenia (8.5%) were comparable to previous studies of reference filgrastim
Aapro, MS, et al. Eur J Cancer. 2011; 47(1): 8-32.Gasćon, P, et al. Support Care Cancer. 2013; 21(10): 2925-32.
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Infliximab-dyyb (Inflectra®)
FDA approval: April 5, 2016
“Key” differences: Approved for 7 of the 8 indications that Remicade® carries
Not labeled for pediatric ulcerative colitis due to orphan drug exclusivity
Initial application (2014) rejected due to “residual uncertainty” regarding differences in bioactivity and immunogenicity, which were addressed in the follow-up application
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125544Orig1s000SumR.pdf. April 5, 2016 (accessed August 13, 2016).
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Infliximab-dyyb (Inflectra®) –Approval Data
Supported by evaluations of analytical similarity and animal studies of pharmacodynamics and toxicity
Preclinical study – Park W, et al.
Compared biosimilar infliximab, U.S. reference product, and E.U. reference product
Pharmacokinetic parameters bioequivalent
No observed differences in safety
Additional PK/PD data reported as “highly similar” in larger clinical studies comparing biosimilar infliximab to the E.U. reference product; safety profiles and immunogenicity were comparable
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125544Orig1s000SumR.pdf. April 5, 2016 (accessed August 13, 2016).
Park, W, et al. Expert Rev Clin Immunol. 2015; 11(S1): S25-31.Park, W, et al. Ann Rheum Dis. 2013; 72:10: 1605-12.
Yoo, DH, et al. Ann Rheum Dis. 2013; 72(10): 1613-20.
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Infliximab-dyyb (Inflectra®) –Approval Data – Rheumatoid Arthritis
Clinical study – Yoo DH, et al.
Conducted in 606 patients with active rheumatoid arthritis despite methotrexate therapy
Randomized 1:1
Biosimilar infliximab or E.U. reference product – 3 mg/kg at weeks 0, 2, 6, and then every 8 weeks
ACR20 responses at week 30, secondary endpoints -comparable
Results at 54 weeks, and at 2 years (after switching to biosimilar) -comparable
Yoo, DH, et al. Ann Rheum Dis. 2013; 72(10): 1613-20.Yoo, DH, et al. Arthritis Res Ther. 2016; 18: 82.
Yoo, DH, et al. Ann Rheum Dis. 2016 Apr 29 [Epub ahead of print].
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Infliximab-dyyb (Inflectra®) –Approval Data – Ankylosing Spondylitis
Clinical study – Park W, et al.
Conducted in 250 patients with active ankylosing spondylitis
Randomized 1:1
Biosimilar infliximab or E.U. reference product – 5 mg/kg at weeks 0, 2, 6, and then every 8 weeks
Primary endpoint was PK evaluation
ASAS20/ASAS40 responses at week 30, other secondary endpoints – comparable
Results at 54 weeks - comparable
Park, W, et al. Ann Rheum Dis. 2013; 72:10: 1605-12.Park, W, et al. Arthritis Res Ther. 2016; 18: 25.
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Infliximab-dyyb (Inflectra®) –Barriers to Market Availability?
Traynor, K. Am J Health Syst Pharm. 2016; 73(10): 604, 606.http://www.medpagetoday.com/rheumatology/arthritis/57239. April 7, 2016 (accessed August 14, 2016).
http://bioloquitur.com/newly-approved-biosimilar-inflectra-market-launch-held-up-in-court/#page=1. April 12, 2016 (accessed August 14, 2016)
http://www.fiercepharma.com/pharma/j-j-braces-for-biosim-attack-after-losing-last-ditch-remicade-patent-fight. August 17, 2016 (accessed Augsut 30, 2016).
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Biosimilars Walking a Fine Line?
http://ashclinicalnews.org/fda-declines-approval-biosimilar-pegfilgrastim. August 1, 2016 (accessed August 14, 2016).http://www.gabionline.net/Biosimilars/News/FDA-rejects-Sandoz-s-biosimilar-pegfilgrastim-application. August 5, 2016 (accessed
August 25, 2016).http://www.bna.com/fda-response-delays-n57982062818/. October 28, 2015 (accessed August 14, 2016).
http://www.sandoz.com/media_center/press_releases_news/global_news/2016-07-13-sandoz-biosimilar-etanercept-recommended-by-fda-advisory-committee-for-approval.shtml. July 13, 2016 (accessed August 25, 2016).
http://www.gabionline.net/Biosimilars/News/FDA-advisors-recommend-approval-of-Sandoz-s-etanercept-biosimilar. July 29, 2016 (accessed August 25, 2016).
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What’s in the Pipeline?
Reference Product Biosimilar DeveloperAdalimumab (Humira®) Sandoz/Novartis, Amgen, Pfizer,
Biogen, Samsung Bioepis/MerckBevacizumab (Avastin®) Amgen, Pfizer, Samsung Bioepis/MerckCetuximab (Erbitux®) AmgenEpoetin alfa (Procrit®, Epogen®) Sandoz/NovartisInfliximab (Remicade®) Sandoz/Novartis, Amgen, Samsung
Bioepis/MerckRituximab (Rituxan®) Sandoz/Novartis, Amgen, PfizerTrastuzumab (Herceptin®) Amgen, Pfizer, Samsung Bioepis/Merck
Others in development…
Tocilizumab, golimumab, abatacept…
What about “biosimilar” insulins? – insulin glargine (Basaglar ®), MK-1293
http://www.sandoz-biosimilars.com/en/aboutus/biosimilars-pipeline.shtml. Accessed August 25, 2016.http://www.amgenpipeline.com/pipeline/. April 1, 2016 (accessed August 25, 2016).
http://www.pfizerbiosimilars.com/pfizer-pipeline. Accessed August 25, 2016.https://www.biogen.com/en_us/about-biogen/biosimilars.html. Accessed August 25, 2016.
http://www.gabionline.net/Biosimilars/News/Merck-outlines-biosimilars-programme. April 17, 2015 (accessed August 25, 2016).http://www.gabionline.net/Biosimilars/News/Samsung-Bioepis-starts-phase-III-trial-for-bevacizumab-biosimilar. April 19, 2016
(accessed August 25, 2016).
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What’s in the Pipeline?
http://www.imshealth.com/files/web/IMSH%20Institute/Healthcare%20Briefs/Documents/IMS_Institute_Biosimilar_Brief_March_2016.pdf. March 2016 (accessed August 25, 2016).
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KEY CONSIDERATIONS IN BIOSIMILAR REVIEW
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What to Consider When Reviewing Biosimilars for Formulary Inclusion
Safety & Efficacy
• Product characteristics
• Clinical data• Immunogenicity• Pharmacovigilance for
safety concerns
Manufacturer Considerations
• Medication availability• History of shortages
or recalls• Handling practices• Supply chain security• Anti-counterfeit
protection
Hospital & Patient Factors
• Packaging and labeling
• Product storage• Product administration• Interchangeability• Variety (extrapolation)
of indications• Product naming• Information
technology support• Economic
considerations• Patient education
Griffith, N, et al. Hosp Pharm. 2014; 49(9): 813-25.
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Safety & Efficiacy
Key Questions
Does the clinical data (pre-approval, post-approval, international) available support the indications for which the biosimilar has been approved and is being considered for formulary inclusion? What about use of the biosimilar in off-label indications?
How will your health system address pharmacovigilance concerns regarding potential differences in immunogenicity and other adverse effects?
Griffith, N, et al. Hosp Pharm. 2014; 49(9): 813-25.
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Manufacturer Considerations
Key Questions
Will the manufacturer be able to maintain a reliable supply and adequate production of the biosimilar to meet demand for its anticipated usage?
Does the manufacturer have a recent history of shortages or recalls that would decrease your health system’s confidence in the biosimilar’s availability?
Griffith, N, et al. Hosp Pharm. 2014; 49(9): 813-25.
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Hospital & Patient Factors
Key Questions
Are there any differences in packaging, shelf life, storage requirements or routes of administration between the biosimilar and reference product?How should interchangeability of the biosimilar be addressed?
Will the biosimilar being reviewed be included on formulary for all indications for which the reference product is approved, if different?
How will the naming of the biosimilar affect adverse eventreporting/tracking and its inclusion in your health system’s IT systems?What cost factors, besides acquisition cost, should be considered?
Griffith, N, et al. Hosp Pharm. 2014; 49(9): 813-25.
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Interchangeability
The biological product is biosimilar to the reference product, can be expected to produce the same clinical result as the reference product in any given patient, and…the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.
Impact of state substitution laws?
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM216146.pdf. (accessed August 13, 2016).
http://www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx. August 1, 2016 (accessed 2016 Aug 14).
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Interchangeability
http://www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx. August 1, 2016 (accessed 2016 Aug 14).
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Interchangeability – The Shift is On
CVS Health’s 2017 formulary management strategy
Filgrastim-sndz (Zarxio®) replacing filgrastim (Neupogen®)
Insulin glargine (Basaglar®) replacing insulin glargine (Lantus®)
Chingcuanco F, et al.
Systematic review of clinical data for biosimilar and reference TNF- inhibitors
Biosimilarity supported by pharmacokinetic and adverse effect variable as well as major clinical efficacy endpoints
“Despite the paucity of studies, the existing evidence supports the biosimilarity and interchangeability of these newly developed TNF- inhibitor products, especially for the treatment of patients with RA.
https://www.biosimilarsresourcecenter.org/cvs-health-turns-biosimilars-follow-biologics-2017-formulary/. August 3, 2016 (accessed August 29, 2016).
http://investors.cvshealth.com/~/media/Files/C/CVS-IR-v3/documents/02-aug-2016/2017-standard-formulary-list-of-removals-and-updates.pdf. Accessed August 29, 2016
Chingcuanco, F, et al. Ann Intern Med. August 2, 2016 [Epub ahead of print].
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Resources for Pharmacists
FDA’s Purple Book
FDA Website –Information on Biosimilars
ASHP Resource Center on Biosimilars
Partnership between 8 pharmacy-related associations
http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/ucm411418.htm. July 19, 2016 (accessed August 14, 2016).
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/default.htm. May 10, 2016 (accessed August 14, 2016).
http://www.ashp.org/menu/PracticePolicy/ResourceCenters/Emerging-Sciences/Biosimilars.apx. Accessed August 14, 2016.https://www.biosimilarsresourcecenter.org. Accessed August 29, 2016.
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Audience Response Question #2
Filgrastim-sndz (Zarxio®) is considered interchangeable by the Food & Drug Administration.
a. True
b. False
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References Frequently asked questions about therapeutic biological products. (2016, July 7). Retrieved August 13, 2016, from
http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/ucm113522.htm.
Schumock, G.T., Li, E.C., Suda, K.J., Wiest, M.D., Subbings, J, Matusiak, L.M., …Vermeulen, L.C. (2016). National trends in prescription drug expenditures and projections for 2016. Am J Health Syst Pharm, 73(14), 1058-1075.
Lucio, S.D., Stevenson, J.G., & Hoffman, J.M. (2013). Biosimilars: implications for health-system pharmacists. Am J Health Syst Pharm, 70(15), 2004-2017.
US $54 billion worth of biosimilar patents expiring before 2020. (2011, September 30). Retrieved August 13, 2016, from http://www.gabionline.net/Biosimilars/Research/US-54-billion-worth-of-biosimilar-patents-expiring-before-2020.
The biggest drug patient losses for 2013. (2013, May 17). Retrieved August 13, 2016, from http://www.gabionline.net/Generics/General/The-biggest-drug-patent-losses-for-2013.
Scientific considerations in demonstrating biosimilarity to a reference product [PDF document]. (2015, April). Retrieved August 13, 2016, from http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf.
Sections 7001-7003 (Biologics Price Competition and Innovation Act of 2009) of the Patient Protection and Affordable Care Act (Public Law No. 111-148) [PDF document]. Retrieved August 13, 2016, from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM216146.pdf.
Mellstedt, H.M., Niederwieser, D., & Ludwig, H. (2008). The challenge of biosimilars. Ann Oncol, 19(3), 411-419. Q5E comparability of biotechnological/biological products subject to changes in their manufacturing process [PDF
document]. (2005, June). Retrieved August 25, 2016, from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073476.pdf
Bioengineering and biosimilars. Retrieved August 30, 2016, from www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf.
Biosimilars: questions and answers regarding implementation of the Biologics Price Competition and Innovation Act of 2009 [PDF document]. (2015, April). Retrieved August 13, 2016, from http://www.fda.gov/downloads/Drug/GuidanceComplianceRegulatory/Information/Guidances/UCM444661.pdf.
Nonproprietary naming of biological products [PDF document]. (2015, August). Retrieved August 25, 2016, from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM459987.pdf.
Biological qualifer: an INN proposal [PDF document]. (2015, October). Retrieved August 25, 2016, from http://www.who.int/medicines/services/inn/WHO_INN_BQ_proposal_2015.pdf?ua=1.
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References EU majority says same INNs for biosimilars. (2014, February 28). Retrieved August 25, 2016, from
http://www.gabionline.net/Biosimilars/General/EU-majority-says-same-INNs-for-biosimilars. Tomaszewski, D. (2016). Biosimilar naming conventions: pharmacist perceptions and impact on confidence in
dispensing biologics. J Manag Care Spec Pharm, 22(8), 919-926. Filgrastim-sndz (Zarxio®) [package insert]. Princeton, NJ: Sandoz, Inc.; 2016. Filgrastim (Neupogen®) [package insert]. Thousand Oaks, CA: Amgen, Inc.; 2016. Summary review [PDF document]. (2015, March 6). Retrieved August 13, 2016, from
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125553Orig1s000SumR.pdf. Sörgel, F, Schwebig, A, Holzmann, J, Prasch, S, Singh, P, & Kinzig, M. (2015). Comparability of biosimilar filgrastim with
originator filgrastim: protein characterization, pharmacodynamics, and pharmacokinetics. BioDrugs, 29(2): 123-131. Blackwell, K., Semiglazov, V., Krasnozhon, D., Davidenko, I., Nelyubina, L., Nakov, R., …Harbeck, N. (2015).
Comparison of EP2006, a filgrastim biosimilar, to the reference: a phase III, randomized, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. Ann Oncol, 26(9): 1948-1953.
Aapro, M.S., Bohlius, J., Cameron, D.A., Dal Lago, L., Donnelly, J.P., Kearney, N., …Zielinski, C. (2011). 2010 update of the EORTC guidelines for the use of granulocyte-colony stimluating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer, 47(1), 8-32.
Gasćon P., Tesch, H., Verpoort, K., Rosati, M.S., Salesi, N., Agrawal, S., …Turner, M. (2013). Clinical experience with Zarzio® in Europe: what have we learned? Support Care Cancer, 21(10), 2925-2932.
Summary review [PDF document]. (2015, April 5). Retrieved August 13, 2016, from http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125544Orig1s000SumR.pdf.
Park, W., Lee, S.J., Yun, J., & Yoo, D.H. (2015). Comparison of the pharmacokinetics and safety of three formulations of infliximab (CT-P13, EU-approved reference infliximab and the US-licensed reference infliximab) in healthy subjects: a randomized, double-blind, three-arm, parallel-group, single-dose, phase I study. Expert Rev Clin Immunol, 11(sup1), 25-31.
Park, W., Hrycaj, P., Jeka, S., Kovalenko, V., Lysenko, G., Miranda, P., …Braun, J. (2013). A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis, 72(10), 1605-1612.
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References Yoo, D.H., Hrycaj, P. Miranda, P., Ramiterre, E., Piotrowski, M., Shevchuk, S., …Müller-Ladner, U. (2013). A
randomized, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis, 72(10), 1613-20.
Yoo, D.H., Racewicz, A., Brzezicki, J., Yatsyshyn, R., Arteaga, E.T., Baranauskaite, A., …Park, W. (2016). A phase III randomized study to evaluate the efficacy and safety of CT-P13 compared with reference infliximab in patients with active rheumatoid arthritis: 54-week results from the PLANETRA study. Arthritis Res Ther, 18, 82.
Yoo, D.H., Prodanovic, N., Jaworski, J., Miranda, P., Ramiterre, E., Lanzon, A., …Park, W. (2016). Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: comparison between switching from reference inflximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study. Ann Rheum Dis. Advance online publication. doi: 10.1136/annrheumdis-2015-208786.
Park, W., Yoo, D.H., Jaworski, J., Brzezicki, J., Gnylorybov, A., Kadinov, V., …Braun, J. (2016). Comparable long-term efficacy, as assessed by patient-reported outcomes, safety and pharmacokinetics, of CT-P13 and reference infliximab in patients with ankylosing spondylitis: 54-week results from the randomized, parallel-group PLANETAS study. Arthritis Res Ther, 18, 25.
Traynor, K. (2016). FDA approves biosimilar version of infliximab. Am J Health Syst Pharm, 73(10), 604, 606. Walsh, N. (2016, April 7). A rocky start for biosimilar Inflectra? Retrieved August 14, 2016, from
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http://bioloquitur.com/newly-approved-biosimilar-inflectra-market-launch-held-up-in-court/#page=1. Staton, T. (2016, August 17). J&J braces for biosim attack after losing last-ditch Remicade patent fight. Retrieved August
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Additional Resources
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Dranitsaris, G., Dorward, K., Hatzimichael, E., & Amir, E. (2013). Clinical trial design in biosimilar drug development. Invest New Drugs, 31(2), 479-487.
Li, E., Ramanan, S., & Green, L. (2015). Pharmacist substitution of biological products: issues and considerations. J Manag Care Spec Pharm, 21(7): 532-539.
Li, E.C. & Stevenson, J.G. (2015, December 7). Biosimilars-the time is now: challenges and opportunities for pharmacists [PowerPoint slides]. Retrieved from http://elearning.ashp.org/products/5153/biosimilarsthe-time-is-now-challenges-and-opportunities-for-pharmacists.
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