CMDAT Research Foundation
CMDAT Research Foundation 

Biosimilars 101 

What are biologic products?


Biologic products, or sometimes called “biologics”, include various complex products such as recombinant therapeutic proteins, vaccines, somatic cells, gene therapy etc. Biologic products, including biosimilars have become an important part of cancer therapy worldwide1-5. These products are also used to manage various side effects from cancer treatment. 


Biologics differ from traditional small-molecule drugs like aspirin. They are much more complex and much more difficult to manufacture1-3. Comparing small-molecule drugs and biologic products is like comparing a paper with some text to the most recent generation computer that you use in your office. This is how complex the biologics are.


Unfortunately, knowledge gaps may exist among oncology/hematology team members regarding various aspects related to biologic products, including biosimilars such as safety or interchangeability6-8. Such gaps may potentially prevent oncology patients from access to optimal combination therapy for cancer.


What are biosimilars?


What is biosimilarity?  Let’s take a look at the definition first.


‘‘The biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components, and there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product”9.


Suppose that you need to make a copy of a paper with text. You may simply use a copy machine and you will get the exact same copy of your text. Similarly, you can get an exact copy of a small-molecule brand name drug, also called a “generic”.


Copying biologic products more closely resembles ordering another one of the most recent generation computers with highly similar specifications. The new computer may vary slightly from your current model but will hold to the same performance standards. For example, the replacement computer will likely have slightly different design or other insignificant differences. Nevertheless, the replacement computer is fully capable to perform nearly exactly as the original.


The scenario with the replacement computer is similar to biologic products. That’s because unlike small-molecule drugs, biologic products are manufactured from living organisms and cannot be exactly copied. However, a highly similar copy (“biosimilar”) of the referenced biologic product (like the replacement computer that you ordered), could be developed. This copy will be highly similar to the referenced biologic product in many important aspects such as efficacy, safety and purity but will not be identical. Therefore, biosimilars can be viewed as therapeutic alternatives to a referenced product. However, because of the difference in the manufacturing process, they are not identical to the referenced biologic products. Therefore, biosimilars cannot be classified as generic drugs1, 3.


How are biosimilars regulated in the US?


According to the Biologics Price Competition and Innovation, there should be sufficient evidence to demonstrate biological products “biosimilarity” such as “safety, purity and potency for one or more appropriate conditions of use for which the reference product is licensed”10. Furthermore, the FDA can approve a biosimilar if it has no clinically meaningful differences with regard to efficacy or safety from the referenced biological product. Finally, a biosimilar must have the same important characteristics of the referenced product such as strength or mechanism of action to get such approval10.


Safety monitoring regarding biosimilars


First, we should briefly discuss immunogenicity and pharmacovigilance (also known as “drug safety”). Let's take a look at the definition of immunogenicity.


“Immunogenicity is the ability of a particular substance, such as an antigen or epitope, to provoke an immune response in the body of a human or animal.11


Therefore, although biologic products are generally non-toxic and well-tolerated, they can still trigger certain immune responses that may become an ongoing safety concern12. In addition, immunogenicity may directly impact efficacy. Various factors may impact immunogenicity such as disease- and patient-related factors or the route of administration13.


What is pharmacovigilance? It is “the science and activities relating to the detection, assessment, understand and prevention of adverse effects or any other drug related problem”14, 15.


According to the FDA, a manufacturer must follow a specific drug safety plan which may require a postmarket surveillance of adverse events. In addition, a manufacturer may be required to follow specific product registries or report serious adverse events in an expedited manner. Other requirements may include conducting population-based studies or clinical trials.  In addition, any suspected serious adverse reactions associated with use of biosimilar products should be reported by the treating physician and other prescribers16.


Therefore, the issue of drug safety is important not only to patients and treating physicians but also to industry. Even after a biologic product (including a biosimilar) is approved, its clinical safety must be monitored continuously by all parties. To date, there are no known specific safety issues related to approved and marketed biosimilars16.


Interchangeability, automatic substitution versus prescriber facilitated switching


Pharmacists may sometime substitute a prescription medication for a generic one without obtaining a prior consent of the treating physician. This is also known as “automatic substitution”16, 17.


Colorado has passed biosimilars substitution bills in 2015. One of bills states that the dispensing pharmacist or the pharmacist's designee must communicate “within a reasonable time to the prescribing practitioner the specific biological product dispensed to the patient including the name and manufacturer of the biological product.18. In addition, “if the FDA has determined that the biological product is interchangeable with the prescribed biological product and if the practitioner has not indicated that the prescription must be dispensed as written, provides the dispensing pharmacist or the pharmacist's designee must communicate to the prescribing practitioner the specific biological product dispensed to the patient, provides situations when communication is not necessary10.”


In the future, if a pharmacist in Colorado decides to substitute a referenced biologic product for a biosimilar, he/she should notify the prescribing physician and make a patient aware of such substitution. Prescribing physicians may still write “dispense as written” if they do not want a biologic substitution made. Remember, the substituted product must be designated as interchangeable by the FDA.


What is interchangeability?


According to the FDA, the term “interchangeable” means that the product is “biosimilar to an FDA-approved reference product, and can be expected to produce the same clinical result as the reference product in any given patient. An interchangeable product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. … In addition, for a biological product that is administered more than once to an individual, the risk in terms of safety or efficacy of alternating or switching between the biological product and the reference product will not be greater than the risk of using the reference product without alternating or switching.19


In other words, suppose that a given patient needs to receive the course of treatment of a biologic produc more than once. Such patient may receive referenced biologic products only, switch to interchangeable products, or, alternate between the referenced biologics and interchangeable products. In the case of switch or alternate, interchangeable products are expected to have no less efficacy and no more safety risk when switched or alternated with the referenced product (the safety and efficacy observed when alternating or switching between the two remain the same).


Although there are no interchangeable biosimilars in the U.S. as of September 2017, according to the FDA, they are expected to come to market within the next two years or sooner20. The FDA Purple Book will then indicate if a particular biosimilar product has become “interchangeable”21.


A treating physician should be actively involved in the decision to switch to a biosimilar product because each patient’s scenario is unique. Such decision should be also backed by science and should not depend only upon whether a biosimilar product is interchangeable or not. 


Financial advantages to use biosimilars


The average daily cost of cytotoxic chemotherapy is only $12. However, such cost of a biologic product could be as high as $45. Moreover, the average total costs of cancer treatment per year can be higher than the median U.S. household income.22, 23 In Europe, biosimilars provide as much as 30% cost savings in healthcare. Researchers estimate that such savings could be even higher in other countries including the U.S22-24. The U.S. Healthcare system savings from the use of biosimilars in the next several years could be as much as $250 billion dollars25.


Multiple factors such as various copay or patient assistance programs will likely affect overall savings resulting from introduction of biosimilars26. Nevertheless, lower cost of biosimilar products as compared to the licensed biologic drugs may help to improve many issues such as adherence to treatment among oncology patients, overall access to cancer treatment, and enhance price competition to biologics overall22-24, 27. For example, biosimilars have become more popular in Europe than in the U.S. As a result, European patients’ access to biologic therapy has increased by nearly 50%28.


Potential impact of biosimilars on cancer care


Cancer can be approached with different treatment options such as chemotherapy, radiotherapy, surgery and more recently, biologic therapy. Each option has its own advantages and disadvantages. For example, surgery may be more suitable for local tumors rather than for disseminated disease. Chemotherapy, while being effective for many types of cancer, could be also toxic to the body and subject to drug shortage. Biologic products while being very effective to repair immune response, when used alone, may not be sufficient to fight cancer. In addition, biologic products may have fewer side effects as compared to toxic chemotherapy but they are usually more expensive29-31.


However, when some of these treatment options are combined, they may become more effective. For example, both chemotherapy and radiation are known to compromise a patient’s immune system. At the same time, evidence suggests that a combination of biologic and chemotherapy could improve antitumor immunity31-33. Furthermore, biologics may stimulate the immune system to fight cancer cells, therefore, they should be started at the beginning of the treatment33-35.  In addition, it is important to remember that biologic agents can be also used as supportive care of cancer.


Unfortunately one of the problems that an oncology/hematology team may encounter in a clinical practice is drug shortage36. Many factors, such as supply delays or various manufacturing problems, may cause such shortage36. This problem affects traditional chemotherapy drugs, but biologic products may also be affected by shortage. According to the recent survey of medical doctors who prescribe anticancer medications, more than 80% of them could not treat with a medication of choice due to the shortage problem37. Such shortage may also affect cost of cancer treatment because of the change in treatment options. As the result, patient care is ultimately compromised. The introduction and approval of biosimilars aimed to treat cancer may provide additional treatment options for patients with cancer. Therefore, it may help to reduce shortage of cancer drugs. Of note, a recent survey of the US oncologists suggests that availability of some biosimilars would increase their use in treating some forms of breast cancer38.


Another problem requiring discussion concerns the geriatric population diagnosed with cancer. As our population ages, there will be more elderly patients diagnosed with various types of cancer. Unfortunately, about one third of elderly patients diagnosed with cancer do not receive any cancer treatment39. On one hand, elderly patients diagnosed with cancer may have a different attitude toward aggressive chemotherapy compared to younger patients40. On the other hand, toxic chemotherapy may not be well tolerated by older patients with cancer because of the presence of other chronic diseases41. According to some reports, a combination of a biologic product and less intensive chemotherapy could be more beneficial to patients above 80 years old42, 43.


In conclusion, biological products, including biosimilars, have become an important part of current cancer therapy worldwide5, 44, 45. Recent surveys of health professionals suggest considerable interest in the subject of biosimilars among physicians, nurses and pharmacists7, 46-49. The development and approval of biosimilars in the U.S. may enhance market competition in the area of biologic products. This, in turn, will improve patient access to these products and provide additional treatment options to patients diagnosed with cancer. Oncologists and hematologists as well as oncology/hematology team members are expected to play an important role in reporting any suspected adverse reactions associated with the use of biologic products, including biosimilars. These professionals should also become aware of current trends and updates related to the role of biosmilar products in the optimal combination therapy for cancer.





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3.         Schellekens H, Smolen JS, Dicato M, Rifkin RM. Safety and efficacy of biosimilars in oncology. Lancet Oncol. 2016;17:e502-e509

4.         Roe H. The rise of biosimilars in cancer care. Br J Nurs. 2015;24:S28-29

5.         Carroll J. Europe offers example for approving biosimilars. Manag Care. 2013;22:4-5

6.         Ade A, Bourdon O, Bussieres JF. A survey of pharmacists' knowledge and views of biosimilars in quebec and france. Ann Pharm Fr. 2017

7.         Barsell A, Rengifo-Pardo M, Ehrlich A. A survey assessment of us dermatologists' perception of biosimilars. J Drugs Dermatol. 2017;16:612-615

8.         Beck M, Michel B, Rybarczyk-Vigouret MC, Leveque D, Sordet C, Sibilia J, Velten M. Rheumatologists' perceptions of biosimilar medicines prescription: Findings from a french web-based survey. BioDrugs. 2016;30:585-592

9.         U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

April 2015 Biosimilarity

Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Guidance for Industry


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11.       Wikipedia, the free encyclopedia. Immunogenicity. Accessed August 2017.

12.       Ben-Horin S, Heap GA, Ahmad T, Kim H, Kwon T, Chowers Y. The immunogenicity of biosimilar infliximab: Can we extrapolate the data across indications? Expert Rev Gastroenterol Hepatol. 2015;9 Suppl 1:27-34

13.       Timian S. Whistleblowing protections for colorado nurses: An overview of "whistleblowing" and federal and state law. Colo Nurse. 1999;99:6-7

14.       Casadevall N, Edwards IR, Felix T, Graze PR, Litten JB, Strober BE, Warnock DG. Pharmacovigilance and biosimilars: Considerations, needs and challenges. Expert Opin Biol Ther. 2013;13:1039-1047

15.       Zuniga L, Calvo B. Biosimilars: Pharmacovigilance and risk management. Pharmacoepidemiol Drug Saf. 2010;19:661-669

16.       Leung LK, Mok K, Liu C, Chan SL. What do oncologists need to know about biosimilar products? Chin J Cancer. 2016;35:91

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18.       Baird NL, Cohrs RJ. 2017 colorado alphaherpesvirus latency society symposium. J Neurovirol. 2017

19.       Cicutto L, Gleason M, Haas-Howard C, Jenkins-Nygren L, Labonde S, Patrick K. Competency-based framework and continuing education for preparing a skilled school health workforce for asthma care: The colorado experience. J Sch Nurs. 2017;33:277-284

20.       Calder WJ, Shuman B. Extensive wildfires, climate change, and an abrupt state change in subalpine ribbon forests, colorado. Ecology. 2017

21.       Sabatelli AD, Alpha-Cobb CJ. Will purple become the new orange? The new fda purple book for biologics: What does the future hold? Pharm Pat Anal. 2015;4:63-68

22.       Mehr SR, Brook RA. Factors influencing the economics of biosimilars in the us. J Med Econ. 2017:1-7

23.       Blackstone EA, Joseph PF. The economics of biosimilars. Am Health Drug Benefits. 2013;6:469-478

24.       Simoens S. Health economics of market access for biopharmaceuticals and biosimilars. J Med Econ. 2009;12:211-218

25.       Dusing SC, Brown S. Commentary on "therapy use for children with developmental conditions: Analysis of colorado medicaid data". Pediatr Phys Ther. 2017;29:199

26.       Rumore MM, Randy Vogenberg F. Biosimilars: Still not quite ready for prime time. P T. 2016;41:366-375

27.       McCamish M, Yoon W, McKay J. Biosimilars: Biologics that meet patients' needs and healthcare economics. Am J Manag Care. 2016;22:S439-S442

28.       Kakefuda I, Stallones L. Comparisons of colorado women's cancer screening practices by residence: Metropolitan, non-metropolitan, and farm. J Agric Saf Health. 2006;12:59-69

29.       Plosker GL, Figgitt DP. Rituximab: A review of its use in non-hodgkin's lymphoma and chronic lymphocytic leukaemia. Drugs. 2003;63:803-843

30.       Kanter M, Martinez O, Lindsay G, Andrews K, Denver C. Proactive office encounter: A systematic approach to preventive and chronic care at every patient encounter. Perm J. 2010;14:38-43

31.       Wang M, Fayad L, Wagner-Bartak N, Zhang L, Hagemeister F, Neelapu SS, Samaniego F, McLaughlin P, Fanale M, Younes A, Cabanillas F, Fowler N, Newberry KJ, Sun L, Young KH, Champlin R, Kwak L, Feng L, Badillo M, Bejarano M, Hartig K, Chen W, Chen Y, Byrne C, Bell N, Zeldis J, Romaguera J. Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: A phase 1/2 clinical trial. Lancet Oncol. 2012;13:716-723

32.       Baxevanis CN, Perez SA, Papamichail M. Combinatorial treatments including vaccines, chemotherapy and monoclonal antibodies for cancer therapy. Cancer Immunol Immunother. 2009;58:317-324

33.       Schuster M, Nechansky A, Kircheis R. Cancer immunotherapy. Biotechnol J. 2006;1:138-147

34.       Ruan J, Martin P, Shah B, Schuster SJ, Smith SM, Furman RR, Christos P, Rodriguez A, Svoboda J, Lewis J, Katz O, Coleman M, Leonard JP. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015;373:1835-1844

35.       Raedler LA. Zarxio (filgrastim-sndz): First biosimilar approved in the united states. Am Health Drug Benefits. 2016;9:150-154

36.       Li E, Subramanian J, Anderson S, Thomas D, McKinley J, Jacobs IA. Development of biosimilars in an era of oncologic drug shortages. Drug Des Devel Ther. 2015;9:3247-3255

37.       Gogineni K, Shuman KL, Emanuel EJ. Survey of oncologists about shortages of cancer drugs. N Engl J Med. 2013;369:2463-2464

38.       Lammers P, Criscitiello C, Curigliano G, Jacobs I. Barriers to the use of trastuzumab for her2+ breast cancer and the potential impact of biosimilars: A physician survey in the united states and emerging markets. Pharmaceuticals (Basel). 2014;7:943-953

39.       Hamlin PA, Satram-Hoang S, Reyes C, Hoang KQ, Guduru SR, Skettino S. Treatment patterns and comparative effectiveness in elderly diffuse large b-cell lymphoma patients: A surveillance, epidemiology, and end results-medicare analysis. Oncologist. 2014;19:1249-1257

40.       Oxnard GR, Fidias P, Muzikansky A, Sequist LV. Non-small cell lung cancer in octogenarians: Treatment practices and preferences. J Thorac Oncol. 2007;2:1029-1035

41.       Nabhan C, Smith SM, Helenowski I, Ramsdale E, Parsons B, Karmali R, Feliciano J, Hanson B, Smith S, McKoy J, Larsen A, Hantel A, Gregory S, Evens AM. Analysis of very elderly (>/=80 years) non-hodgkin lymphoma: Impact of functional status and co-morbidities on outcome. Br J Haematol. 2012;156:196-204

42.       Peyrade F, Jardin F, Thieblemont C, Thyss A, Emile JF, Castaigne S, Coiffier B, Haioun C, Bologna S, Fitoussi O, Lepeu G, Fruchart C, Bordessoule D, Blanc M, Delarue R, Janvier M, Salles B, Andre M, Fournier M, Gaulard P, Tilly H. Attenuated immunochemotherapy regimen (r-minichop) in elderly patients older than 80 years with diffuse large b-cell lymphoma: A multicentre, single-arm, phase 2 trial. Lancet Oncol. 2011;12:460-468

43.       Weidmann E, Neumann A, Fauth F, Atmaca A, Al-Batran SE, Pauligk C, Jager E. Phase ii study of bendamustine in combination with rituximab as first-line treatment in patients 80 years or older with aggressive b-cell lymphomas. Ann Oncol. 2011;22:1839-1844

44.       Tsai WC. Update on biosimilars in asia. Curr Rheumatol Rep. 2017;19:47

45.       Camacho LH. Current status of biosimilars in oncology. Drugs. 2017

46.       Ade A, Bourdon O, Bussieres JF. A survey of pharmacists' knowledge and views of biosimilars in quebec and france. Ann Pharm Fr. 2017;75:267-275

47.       Narayanan S, Nag S. Likelihood of use and perception towards biosimilars in rheumatoid arthritis: A global survey of rheumatologists. Clin Exp Rheumatol. 2016;34:S9-11

48.       Grabowski D, Henderson B, Lam D, Keystone EC, Thorne C, Jamal S, Pope J, Haraoui B, Lin D, Revers L. Attitudes towards subsequent entry biologics/biosimilars: A survey of canadian rheumatologists. Clin Rheumatol. 2015;34:1427-1433

49.       Chapman SR, Fitzpatrick RW, Aladul MI. Knowledge, attitude and practice of healthcare professionals towards infliximab and insulin glargine biosimilars: Result of a uk web-based survey. BMJ Open. 2017;7:e016730




























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