Biosimilars: When is their use appropriate?

Investigating the
use of Tbo-filgrastim for pediatric neutropenia.
The introduction of biologic therapies revolutionized treatment guidelines in many fields
of medicine such as rheumatology, oncology, dermatology, and hematology.1 Due to the
upcoming patent expirations of expensive biologic agents, the focus of the biopharmaceutical
industry has been shifting towards the production of more biosimilar agents. Biosimilars are
drugs that have been shown to have comparable quality, safety, and efficacy to the original
product. The Patient Protection and Affordable Care Act (ACA) amends the Public Health
Service Act (PHS Act) to create an abbreviated licensure pathway for biological products that
are demonstrated to be “biosimilar” to or “interchangeable” with an FDA-approved biologic.
Under this new law, a biological product may be demonstrated to be “biosimilar” if data show
that, among other things, the product is highly similar to an already-approved biological
product.2 In a way biosimilars may be considered the generic forms of biologic agents.
However, biosimilars are highly complex at their molecular level and even slight variations
during the manufacturing of these complex molecules may lead to significant changes in their
safety and efficacy profiles.3 For this reason establishing undeniable comparability to the
original biologic reference product is essential for successful approval of a biosimilar product.
Even slight variations in the production process can lead to significant changes in the product
produced. For example, the FDA rejected Genzyme’s application to scale up production of
Myozyme® from 160 liters to a 2,000 liters because they were concerned about differences in
the carbohydrate structure of the product and required a new biologic license. Whether
biosimilars are truly comparable and interchangeable with original biologic agents in terms of
quality, efficacy and tolerability is still a matter of debate.4 This paper will discuss the ethical
dilemma of using biosimilars in pediatric populations prior to sufficient studies being published
that demonstrate their safety and efficacy in children. Specifically this paper will discuss the
appropriateness of using the new colony stimulating factor biosimilar tbo-filgrastim in place of
Neupogen (filgrastim) for pediatric patients suffering from neutropenia.
The introduction of more biosimilars to the market introduces the potential for drastic
reduction in medication costs and increased treatment availability. As biosimilars enter the
market the added competition will begin to drive the price of these products down.5 The
prospect of saving money has led to changes in many hospital’s formularies. These institutions
recognize the potential to save themselves and their patients money through the
implementation of these new biosimilar products.

Teva is beginning to manufacture a recombinant human granulocyte colony-stimulating
factor (G-CSF), tbo-filgrastim (Granix). The FDA approved this product to reduce the duration of
severe neutropenia in adults with non-myeloid malignancies receiving myelosuppressive
chemotherapy that has led to febrile neutropenia.6 Tbo-filgrastim is not technically considered a
biosimilar to filgrastim because it was filed as a Biologics License Application since a biosimilars
approval pathway had not been established at that time. Despite this technicality, these two
drugs may be considered to be biosimilar because even though they have slight structural
differences, the pharmacokinetic parameters, safety, and efficacy between these two agents do
not significantly differ.7 For this reason many institutions have begun substituting these
medications with confidence that they will be therapeutically equivalent to the original product.
Here is a table deomonstrating that compares the cost effectiveness of these agents and
how institutions may save over 75 dollars by switching to tbofilgrastim for just one dose.8



5 mcg/kg/day
5 mcg/kg/day


WAC ($) for
300mcg/0.5mL (dose
for ≤60 kg patient)
314.80 (0.5mL)

Reduction in the Duration of
Severe Neutropenia (DSN)
compared to placebo
3.2 Days

Price ($) per 1 Day
Reduction in the Duration
of Severe Neutropenia

239.00 (0.5mL)

2.7 Days


Clinical Trials
The FDA approved tbo-filgrastim after having clinical efficacy and safety established
through three randomized clinical studies in patients receiving chemotherapy for breast cancer,
lung cancer, and non-Hodgkin lymphoma. Each of these studies were multinational,
multicenter, randomized, controlled studies. In all three studies, tbo-filgrastim and filgrastim
were administered subcutaneously at 5 mcg/kg/day for five to fourteen days in each cycle of
chemotherapy. These CSFs were started the day after the end of each chemotherapy cycle, and
stopping when an ANC of at least 10x109/L was reached. Each patient was examined over four
to six cycles of chemotherapy. 9,10,11
Each study differed slightly in design. The first study, study XM02- 02 INT, some patients
were initially randomized to a placebo group and received placebo after their first cycle and
then received tbo-filgrastim in all subsequent cycles. In the other two studies, XM02-03-INT and
XM02-04-INT, some patients were randomized to the filgrastim group for their first cycle and
received tbo-filgrastim in all subsequent cycles. 9,10,11

All three studies enrolled adult male and female patients undergoing chemotherapy.
The patient populations differed with respect to the cancer being treated and the
chemotherapy received. The pivotal study, XM02-02-INT, was unique in the fact that only
chemotherapy treatment-naïve patients were enrolled in order to have a standardized patient
population. The treatment groups were similar in each study with regard to demographic and
baseline characteristics. These studies were designed so that the patient populations are
representative of the normal patient population receiving chemotherapy. 9,10,11
During these trials safety assessments were used that included treatment-emergent
adverse events, laboratory tests, physical examinations, vital signs assessments, injection site
reactions, and immunogenicity. All safety variables were then analyzed. The unbiased
assessment of efficacy and safety was ensured by blinding of the investigator and the patient
during the studies. The results of these studies showed that tbo-filgrastim and filgrastim were
similar in almost all parameters and better than placebo. All of these trials were performed in
adults. 9,10,11 The safety and efficacy of tbo- filgrastim has yet to be established in pediatric
patients and reports no current trials investigating the use of tbo- filgrastim in
children. 6,12

The temptation to save money through the use of biosimilars will be something that
appeals to many institutions for years to come. It is important to make responsible decisions
when considering the use of biosimilars. These medications may have the same mechanism of
action, dosing, and pharmacokinetic/pharmacodinamic profiles, but the effects of the slight
differences in their structure will not be completely understood for years. Medications should
only be used for indications and in populations where there is sufficient studies and data to
justify their use. Switching pediatric patients to tbo-filgrastim without sufficient evidence to
justify the substitution is irresponsible. Persons responsible for formulary decisions should drive
medication utilization that is in line with the indication and dosing established by the FDA.

Works Cited
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statement on safety of biologic treatment with monoclonal antibodies and soluble
receptors. Pol Merkur Lekarski. 2014 Jul;37(217):5-9.
2. Information for Consumers (Biosimilars). U.S. Food and Drug Administration.

3. Rathore AS, Bhambure R. Establishing analytical comparability for "biosimilars":
filgrastim as a case study. Anal Bioanal Chem. 2014 Oct;406(26):6569-76. doi:
10.1007/s00216-014-7887-4. Epub 2014 May 28.
4. Declerck PJ1, Darendeliler F, Góth M, Kolouskova S, Micle I, Noordam C, Peterkova V,
Volevodz NN, Zapletalová J, Ranke MB. Biosimilars: controversies as illustrated by rhGH.
Curr Med Res Opin. 2010 May;26(5):1219-29. doi: 10.1185/03007991003719642.
5. Hoffman J, Thomas E, Dombrowski S. A Health-System Pharmacist’s Guide to
Biosimilars: Regulatory, Scientific, and Practical Considerations. ASHP
6. Granix [package insert]. Teva Pharmaceuticals. North Wales, PA 19454. May 2013.
7. Pappas A, Hanna S. TBO-Filgrastim (Granix). Pharmacy Times.
8. Micromedex 2.0 [Internet]. Greenwood Village (CO): Truven Health Analytics Inc; c 2013.
RED BOOK drug. Available from Registration and login
9. del Giglio A, Eniu A, Ganea-Motan D, Topuzov E, Lubenau H. XM02 is superior to placebo
and equivalent to Neupogen in reducing the duration of severe neutropenia and the
incidence of febrile neutropenia in cycle 1 in breast cancer patients receiving
docetaxel/doxorubicin chemotherapy. BMC Cancer. 2008;8:332.
10. Engert A, Griskevicius L, Zyuzgin Y, Lubenau H, del Giglio A. XM02, the first granulocyte
colony-stimulating factor biosimilar, is safe and effective in reducing the duration of
severe neutropenia and incidence of febrile neutropenia in patients with non-Hodgkin
lymphoma receiving chemotherapy. Leuk Lymphoma. 2009;50(3):374-379.
11. Gatzemeier U, Ciuleanu T, Dediu M, Ganea-Motan E, Lubenau H, Del Giglio A. XM02, the
first biosimilar G-CSF, is safe and effective in reducing the duration of severe
neutropenia and incidence of febrile neutropenia in patients with small cell or non-small
cell lung cancer receiving platinum-based chemotherapy. J Thorac Oncol. 2009;4(6):736740
12. Studies found for: Granix and Febrile Neutropenia.