New Drug Updates: Biosimilars. Christopher Allen, PharmD, BCOP Supervising Pharmacist, Infusion Therapy UAB Hospital September 30, 2016

Transcription

1 New Drug Updates: Biosimilars Christopher Allen, PharmD, BCOP Supervising Pharmacist, Infusion Therapy UAB Hospital September 30, 2016

2 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) Page 2

3 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. Page 3

4 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 plications/therapeuticbiologicapplications/ucm htm. July 7, 2016 (accessed August 13, 2016). Schumock GT, et al. Am J Health Syst Pharm. 2016; 73(14): Page 4

5 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): Page 5

6 Potential Growth in Biosimilars? U.S. Patent Expiration Date Adalimumab (Humira ) December 2016 Etanercept (Enbrel ) 2012/2028 Infliximab (Remicade ) 2018 Pegfilgrastim (Neulasta ) Expired Interferon beta-1a (Avonex / Rebif ) Expired Rituximab (Rituxan ) September 2016 Bevacizumab (Avastin ) 2019 Epoetin alfa (Epogen / Procrit ) Expired Trastuzumab (Herceptin ) September 30, 2011 (accessed August 13, 2016). May 17, 2013 (accessed August 13, 2016). Page 6

7 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 April 2015 (accessed August 13, 2016). (accessed August 13, 2016). Page 7

8 Biosimilar Manufacturing An Impossible Copycat Process Mellstedt, H, et al. Ann Oncol. 2008; 19(3): Lucio, SD, et al. Am J Health Syst Pharm. 2013; 70(15): June 2005 (accessed August 25, 2016). Page 8

9 FDA Guidelines for Demonstrating Biosimilarity A Stepwise Approach Comparative process, not a demonstration of therapeutic equivalence! Structure Function Animal Toxicity Human Pharmacokinetics / Pharmacodynamics Clinical Immunogenicity Clinical 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 8.pdf. April 2015 (accessed August 13, 2016). Page 9

10 Totality of the Evidence What s the Difference? Accessed August 30, Page 10

11 FDA Biosimilar Specifications Biosimilar Product Specification Formulation Delivery device/container Routes of administration Indications Strength Comparison with Reference Product May be different May be different May obtain licensure for fewer than all routes of administration for which reference product is licensed May obtain licensure for fewer than all indications for which reference product is licensed Must be the same 1.pdf. April 2015 (accessed August 13, 2016). Page 11

12 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 August 2015 (accessed August 25, 2016). October 2015 (accessed August 25, 2016) February 28, 2014 (accessed August 25, 2016). Tomaszewski D. J Manag Care Spec Pharm. 2016: 22(8): Page 12

13 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 Page 13

14 THE CURRENT BIOSIMILAR PRODUCT LANDSCAPE Page 14

15 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.; Filgrastim (Neupogen ) [package insert]. Thousand Oaks, CA: Amgen, Inc.; March 6, 2015 (accessed August 13, 2016). Page 15

16 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 March 6, 2015 (accessed August 13, 2016). Sörgel, F, et al. BioDrugs. 2015; 29(2): Page 16

17 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): Page 17

18 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): Gasćon, P, et al. Support Care Cancer. 2013; 21(10): Page 18

19 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 April 5, 2016 (accessed August 13, 2016). Page 19

20 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 April 5, 2016 (accessed August 13, 2016). Park, W, et al. Expert Rev Clin Immunol. 2015; 11(S1): S Park, W, et al. Ann Rheum Dis. 2013; 72:10: Yoo, DH, et al. Ann Rheum Dis. 2013; 72(10): Page 20

21 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): Yoo, DH, et al. Arthritis Res Ther. 2016; 18: 82. Yoo, DH, et al. Ann Rheum Dis Apr 29 [Epub ahead of print]. Page 21

22 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: Park, W, et al. Arthritis Res Ther. 2016; 18: 25. Page 22

23 Infliximab-dyyb (Inflectra ) Barriers to Market Availability? Traynor, K. Am J Health Syst Pharm. 2016; 73(10): 604, April 7, 2016 (accessed August 14, 2016). April 12, 2016 (accessed August 14, 2016) August 17, 2016 (accessed Augsut 30, 2016). Page 23

24 Biosimilars Walking a Fine Line? August 1, 2016 (accessed August 14, 2016). August 5, 2016 (accessed August 25, 2016). October 28, 2015 (accessed August 14, 2016). July 13, 2016 (accessed August 25, 2016). July 29, 2016 (accessed August 25, 2016). Page 24

25 What s in the Pipeline? Reference Product Adalimumab (Humira ) Bevacizumab (Avastin ) Cetuximab (Erbitux ) Epoetin alfa (Procrit, Epogen ) Infliximab (Remicade ) Rituximab (Rituxan ) Trastuzumab (Herceptin ) Biosimilar Developer Sandoz/Novartis, Amgen, Pfizer, Biogen, Samsung Bioepis/Merck Amgen, Pfizer, Samsung Bioepis/Merck Amgen Sandoz/Novartis Sandoz/Novartis, Amgen, Samsung Bioepis/Merck Sandoz/Novartis, Amgen, Pfizer Amgen, Pfizer, Samsung Bioepis/Merck Others in development Tocilizumab, golimumab, abatacept What about biosimilar insulins? insulin glargine (Basaglar ), MK Accessed August 25, April 1, 2016 (accessed August 25, 2016). Accessed August 25, Accessed August 25, April 17, 2015 (accessed August 25, 2016). April 19, 2016 (accessed August 25, 2016). Page 25

26 What s in the Pipeline? Biosimilar_Brief_March_2016.pdf. March 2016 (accessed August 25, 2016). Page 26

27 KEY CONSIDERATIONS IN BIOSIMILAR REVIEW Page 27

28 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): Page 28

29 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 offlabel 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): Page 29

30 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): Page 30

31 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 event reporting/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): Page 31

32 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? (accessed August 13, 2016). August 1, 2016 (accessed 2016 Aug 14). Page 32

33 Interchangeability August 1, 2016 (accessed 2016 Aug 14). Page 33

34 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. August 3, 2016 (accessed August 29, 2016). Accessed August 29, 2016 Chingcuanco, F, et al. Ann Intern Med. August 2, 2016 [Epub ahead of print]. Page 34

35 Resources for Pharmacists FDA s Purple Book ASHP Resource Center on Biosimilars FDA Website Information on Biosimilars Partnership between 8 pharmacy-related associations ogicapplications/biosimilars/ucm htm. July 19, 2016 (accessed August 14, 2016). cbiologicapplications/biosimilars/default.htm. May 10, 2016 (accessed August 14, 2016). Accessed August 14, Accessed August 29, Page 35

36 Audience Response Question #2 Filgrastim-sndz (Zarxio ) is considered interchangeable by the Food & Drug Administration. a. True b. False Page 36

37 References Frequently asked questions about therapeutic biological products. (2016, July 7). Retrieved August 13, 2016, from euticbiologicapplications/ucm 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 Am J Health Syst Pharm, 73(14), Lucio, S.D., Stevenson, J.G., & Hoffman, J.M. (2013). Biosimilars: implications for health-system pharmacists. Am J Health Syst Pharm, 70(15), US $54 billion worth of biosimilar patents expiring before (2011, September 30). Retrieved August 13, 2016, from The biggest drug patient losses for (2013, May 17). Retrieved August 13, 2016, from Scientific considerations in demonstrating biosimilarity to a reference product [PDF document]. (2015, April). Retrieved August 13, 2016, from Sections (Biologics Price Competition and Innovation Act of 2009) of the Patient Protection and Affordable Care Act (Public Law No ) [PDF document]. Retrieved August 13, 2016, from Mellstedt, H.M., Niederwieser, D., & Ludwig, H. (2008). The challenge of biosimilars. Ann Oncol, 19(3), Q5E comparability of biotechnological/biological products subject to changes in their manufacturing process [PDF document]. (2005, June). Retrieved August 25, 2016, from Bioengineering and biosimilars. Retrieved August 30, 2016, from 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 Nonproprietary naming of biological products [PDF document]. (2015, August). Retrieved August 25, 2016, from Biological qualifer: an INN proposal [PDF document]. (2015, October). Retrieved August 25, 2016, from Page 37

38 References EU majority says same INNs for biosimilars. (2014, February 28). Retrieved August 25, 2016, from Tomaszewski, D. (2016). Biosimilar naming conventions: pharmacist perceptions and impact on confidence in dispensing biologics. J Manag Care Spec Pharm, 22(8), Filgrastim-sndz (Zarxio ) [package insert]. Princeton, NJ: Sandoz, Inc.; Filgrastim (Neupogen ) [package insert]. Thousand Oaks, CA: Amgen, Inc.; Summary review [PDF document]. (2015, March 6). Retrieved August 13, 2016, from 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): 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): Aapro, M.S., Bohlius, J., Cameron, D.A., Dal Lago, L., Donnelly, J.P., Kearney, N., Zielinski, C. (2011) update of the EORTC guidelines for the use of granulocyte-colony stimluating factor to reduce the incidence of chemotherapyinduced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer, 47(1), 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), Summary review [PDF document]. (2015, April 5). Retrieved August 13, 2016, from 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), 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), Page 38

39 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), 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: /annrheumdis 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 Newly approved biosimilar Inflectra market launch held up in court. (2016, April 12). Retrieved August 14, 2016, from Staton, T. (2016, August 17). J&J braces for biosim attack after losing last-ditch Remicade patent fight. Retrieved August 30, 2016, from FDA declines approval of biosimilar pegfilgrastim. (2016, August 1). Retrieved August 14, 2016, from FDA rejects Sandoz s biosimilar pegfilgrastim application. (2016, August 5). Retrieved August 25, 2016, from Page 39

40 References FDA response delays Pfizer s release of Epogen biosimilar. (2015, October 28). Retrieved August 14, 2016, from Sandoz biosimilar etanercept recommended by FDA advisory committee for approval to treat multiple inflammatory diseases. (2016, July 13). Retrieved August 25, 2016, from FDA advisors recommend approval of Sandoz s etanercept biosimilar. (2016, July 29). Retrieved August 25, 2016, from Sandoz: unrivalled biosimilars pipeline. Retrieved August 25, 2016, from Amgen pipeline. (2016, April 1). Retrieved August 25, 2016, from Pfizer pipeline Retrieved August 25, 2016, from Biosimilars. Retrieved August, 25, 2016, from Merck outlines biosimilars programme. (2015, April 17). Retrieved August 25, 2016, from Samsung Bioepis starts phase III trial for bevacizumab biosimilar. (2016, April 19). Retrieved August 25, 2016, from Delivering on the potential of biosimilar medicines: the role of functioning competitive markets [PDF document]. IMS Institute for Healthcare Informatics. (2016, March). Retrieved August 25, 2016, from March_2016.pdf. Griffith, N., McBride, A., Stevenson, J.G., & Green, L. (2014). Formulary selection criteria for biosimilars: considerations for US health-system pharmacists. Hosp Pharm, 49(9), State laws and legislation related to biologic medications and substitution of biosimilars. (2016, August 1). Retrieved August 14, 2016, from CVS Health turns to biosimilars, follow-on biologics in 2017 formulary. (2016, August 3). Retrieved August 29, 2016, from Page 40

41 References 2017 Standard formulary list of removals and updates [PDF document]. Retrieved August 29, 2016, from Chingcuanco, F., Segal, J.B., Seoyoung, C.K., & Alexander, G.C. (2016). Bioequivalence of biosimliar tumor necrosis factor- inhibitors compared their reference biologics: a systematic review. Ann Intern Med. Advance online publication. doi: /M Purple book: lists of licensed biological products with reference product exclusivity and biosimilarity or interchangeability evaluations. (2016, July 19). Retrieved August 14, 2016, from euticbiologicapplications/biosimilars/ucm htm. Information on biosimilars. (2016, May 10). Retrieved August 14, 2016, from erapeuticbiologicapplications/biosimilars/default.htm. Biosimilars. Retrieved August 14, 2016, from Sciences/Biosimilars.aspx. Biosimilars Resource Center. Retrieved August 29, 2016, from Page 41

42 Additional Resources Bennett, C.L., Chen, B., Hermanson, T., Wyatt, M.D., Schulz, R.M., Georgantopoulos, P., Armitage, J.O. (2014). Regulatory and clinical considerations for biosimilar oncology drugs. Lancet Oncol, 15(13), e Dranitsaris, G., Dorward, K., Hatzimichael, E., & Amir, E. (2013). Clinical trial design in biosimilar drug development. Invest New Drugs, 31(2), Li, E., Ramanan, S., & Green, L. (2015). Pharmacist substitution of biological products: issues and considerations. J Manag Care Spec Pharm, 21(7): Li, E.C. & Stevenson, J.G. (2015, December 7). Biosimilars-the time is now: challenges and opportunities for pharmacists [PowerPoint slides]. Retrieved from Rising drug prices: impact of biosimilars [PDF document]. (2016, May). Retrieved August 29, 2016, from Sherman, R.E. (2012, February 15). Biosimilar biological products [PDF document]. Retrieved August 13, 2016, from Applications/TherapeuticBiologicApplications/Biosimilars/UCM pdf. Weise, M., Bielsky, M.C., De Smet, K., Ehmann, F., Ekman, N., Giezen, T.J., Scheider, C.K. (2012). Biosimilars: what clinicians should know. Blood, 120(26), Weise, M., Kurki, P., Wolff-Holz, E., Bielsky, M.C., & Schneider, C.K. (2014). Biosimilars: the science of extrapolation. Blood, 124(22), Zelentez, A.D., Ahmed, I., Braud, E.L., Cross, J.D., Davenport-Ennis, N.,, Dickinson, B.D., Hoffman, J.M. (2011). NCCN biosimilars white paper: regulatory, scientific, and patient safety perspectives. J Natl Compr Canc Netw, 9(sup4), S1-S22. Page 42