FDA Recommendations for the Naming and Interchangeability of Biosimilars and the Potential Impact on the American Society of Clinical Oncology Guideline Update of 2015: Use of White Blood Cell Growth Factors
Sarah Francis, PharmD
Clinical Pharmacy Specialist, Hematology/Oncology
Memorial Regional Hospital
Hollywood, FL
Ashley Glode, PharmD BCOP
Clinical Oncology Pharmacy Specialist; Assistant Professor
University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences
University of Colorado Anschutz Medical Campus
Aurora, CO
FDA Guidance
In January 2017, the U.S. Food and Drug Administration (FDA) issued a guidance document on the nonproprietary naming of biological products.1 In it the FDA also discusses the impact of biological product naming on pharmacovigilance and the differences between a biosimilar product and an interchangeable product. For a product to be deemed interchangeable, the manufacturer must provide information in the application requesting this type of approval. A product that is interchangeable with the reference product may be substituted without intervention of the prescriber.
The FDA recommends that biological products licensed under the Public Health Service Act contain a nonproprietary name in- cluding an FDA-designated 4-letter suffix that is without meaning.1 Using this guidance, each originator biological product, related biological product, and biosimilar product would have the same core name but with its own unique suffix. This recommendation applies to both previously licensed and newly licensed products, but the process for implementing these recommendations still needs to be determined. This guidance document focuses on naming convention only.
A potential benefit of streamlining the naming process for biologics is the allowance for pharmacovigilence with these products.1 If the products have distinctive names, patients and healthcare providers will be able to more easily and accurately identify specific products. The unique suffix given to each product should decrease the risk of inadvertent substitution of any product that has not yet been determined to be interchangeable. Implementation of this recommendation for naming of biological products should support the standard use of the designated suffix in all areas of practice and minimize incorrect opinions on the safety and effectiveness of biological products.
The concern about inadvertent substitution of these products relates to safety concerns associated with the immunogenicity of biological products.1 Related biological products and biosimilar products may have approvals differing from that of the reference product and may be packaged in different delivery systems. Because of these potential variations from the reference product, it is important to confirm that the correct product is prescribed, dispensed, and administered. The Purple Book is a reference that may be consulted to determine whether the FDA considers a biological product to be biosimilar to or interchangeable with a reference product.
Biologic drugs have a major role in the management of cancer, and with the development of a biosimilar approval pathway, the number of biologic drug approvals has increased. In 2015, the first biosimilar drug approved by the FDA was a white blood cell (WBC) growth factor, filgrastim-sndz (Zarxio), which is a biosimilar to filgrastim (Neupogen), its reference product.2 The naming recommendations for biologics will be implemented in clinical practice following the convention used for filgrastim-sndz.1
Update by the American Society of Clinical Oncology (ASCO)
The evolution of biosimilar drug approvals has required that major organizations update their clinical practice guidelines to incor- porate these new products. In October 2015, ASCO published an update to its 2006 clinical practice guidelines for the use of hematopoietic colony-stimulating factors (CSFs) including these new agents.3 Data from October 2005 to September 2014 were reviewed to update the 2006 guidelines. Although the majority of the manuscript includes an update of the literature that further supports the 2006 recommendations, a few major changes in the 2015 update include recommendations for the use of biosimilar CSFs, modifications to the recommendation of CSF use to allow chemotherapy dose-density, and removal of recommendations for CSFs in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).4
Dosing of CSFs
New to the 2015 guidelines are recommendations for initiation, duration, dosing, and administration of CSFs, including the recently approved biosimilar products. The FDA-approved biosimilar product filgrastim-sndz carries the FDA-labeled indications, warnings, and dosing recommendations that filgrastim has.5 Tbo-filgrastim is a labeled biological product and not a biosimilar; the biosimilar approval pathway had not yet been put into place when the drug was approved in 2013.6 Tbo-filgrastim is approved only to prevent severe neutropenia in patients receiving myelotoxic chemotherapy at a dose of 5 mcg/kg/day subcutaneously beginning 1–3 days after the end of treatment.7 No changes have been made regarding the dose of filgrastim, pegfilgrastim, and sargramostim.
Although administration of pegfilgrastim 1 to 3 days after chemotherapy is still recommended, some recent studies evaluate al- ternatives if this timeframe is not feasible. Alternatives include use of the newly approved pegfilgrastim automated-inject device and administration of pegfilgrastim immediately following (or 4 days after) chemotherapy. In a series of phase 2 randomized controlled trials, administration of same-day pegfilgrastim was compared with administration of pegfilgrastim 24 hours after chemotherapy. In this analysis, same-day pegfilgrastim increased the duration of severe neutropenia compared with next-day pegfilgrastim.8 Two trials also compared pegfilgrastim on day 2 versus day 4. Though one trial showed a reduced incidence of grade 3 or 4 leukopenia with day 4 administration compared to day 2 administration (70% vs. 43.3%, p < .001), the larger of the two studies found no significant difference between day 2 and day 4 administration in rates of leukopenia, febrile neutropenia, or infection.9,10 Although these alternatives may not be more effective than pegfilgrastim administered during days 1 through 3, they should be considered because they provide more benefit than withholding pegfilgrastim entirely.
Differences in Efficacy
As mentioned in the 2006 guidelines, no data suggest that any CSF is overwhelmingly superior to another. One meta-analysis of five randomized controlled trials comparing pegfilgrastim to filgrastim after chemotherapy suggested a decreased incidence of febrile neu- tropenia with pegfilgrastim (relative risk [RR] 0.66, 95% CI, 0.44 to 0.98), but further studies have failed to confirm this benefit.11-15 In the effort to obtain FDA approval of filgrastim-sndz as a biosim- ilar product, filgrastim-sndz was compared to filgrastim following administration of myelotoxic chemotherapy in two phase 3 non-inferiority trials. Both studies concluded that filgrastim-sndz demonstrated efficacy and safety similar to that to filgrastim, showing no statistically significant difference in the duration of severe neutropenia, time to count recovery, or incidence in febrile neutropenia between groups.16,17 Based on these data, the choice of CSF should be determined on the basis of patient convenience, cost, and the clinical scenario.
Increasing the Dose Density of Chemotherapy
In 2006, it was suggested that the use of CSFs to increase dose density showed benefit in node-positive breast cancer and pos- sibly in non-Hodgkin lymphoma, although further confirmation was required before results could be generalized. The 2015 update presented new evidence showing differing results based on cancer type. Outside of a clinical trial, data exist to support CSF use with dose-dense chemotherapy in the adjuvant breast cancer setting as well as with high-dose-intensity methotrexate, vinblastine, doxoru- bicin, and cisplatin in urothelial cancer. The use of CSFs to increase chemotherapy dose density in non-Hodgkin lymphoma is not recommended. Two phase 3 randomized controlled trials compared R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxy- daunomycin], vincristine [Oncovin], prednisolone) given at 14- or 21-day intervals, both of which showed no difference in overall survival or event-free survival with the dose-dense regimen.18,19
Use in Acute Myeloid Leukemia or Myelodysplastic Syndrome
The 2006 guidelines commented on the role of CSF during AML induction, consolidation, and priming, as well as in the treatment of MDS and acute lymphocytic leukemia. The 2015 panel omitted this discussion altogether; thus, no recent literature was presented, nor were recommendations made regarding this matter.3,4
Overall, the 2015 guideline update provided more guidance regarding the role of biosimilar products and ideal candidates for use of CSFs to increase chemotherapy dose density. More data were presented supporting previous recommendations for CSF use during prophylaxis or treatment of neutropenia. No new data, however, have emerged regarding the use of CSFs during concomitant chemotherapy and radiation or following the treatment of radiation injury. The inclusion of the newly approved biosimilar products was an important step in integrating these medications into evidence-based clinical practice. The FDA guidance statement regarding the naming of biological products will allow practitioners to safely prescribe the correct product and will allow for appropriate interchange of products to minimize medication errors. Additional filgrastim-biosimilar products and pegfilgrastim-biosimilar products are being evaluated.20 Additional updates will need to be made to clinical practice guidelines as these agents are added to the market.
References
1. U.S. Department of Health and Human Services, U.S. Food and Drug Administration Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research. Nonproprietary naming of biological products: guidance for industry. https://www.fda.gov/downloads/drugs/guidances/ucm459987.pdf. Accessed January 2017.
2. FDA News Release. FDA approves first biosimilar product Zarxio. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm436648.htm. Last updated: March 6, 2015. Accessed February 1, 2017.
3. Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2015;33(28):3199-212.
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10. Zwick C, Hartmann F, Zeynalova S, et al. Randomized comparison of pegfilgrastim day 4 versus day 2 for the prevention of chemotherapy- induced leukocytopenia. Ann Oncol. 2011;22:1872-7.
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12. Cesaro S, Nesi F, Tridello G, et al. A randomized, non-inferiority study comparing efficacy and safety of a single dose of pegfilgrastim versus daily filgrastim in pediatric patients after autologous peripheral blood stem cell transplant. PLoS One. 2013;8:e53252.
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16. Gatzemeier U, Ciuleanu T, Dediu M, et al. 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;4:736-40.
17. del Giglio A, Eniu A, Ganea-Motan D, et al. 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.
18. Cunningham D, Hawkes EA, Jack A, et al. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet. 2013;381:1817-26.
19. Delarue R, Tilly H, Mounier N, et al. Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol. 2013;14:525-33.
20. U.S. National Institutes of Health. ClinicalTrials.gov. Available from https:// clinicaltrials.gov/. Accessed February 1, 2017.