Skip to main content

Advertisement

SpringerLink
Log in

In Search of Predictors of Switching Between Erythropoiesis-Stimulating Agents in Clinical Practice: A Multi-Regional Cohort Study

  • Original Research Article
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

Background and objectives

Switching between different erythropoiesis-stimulating agents (ESAs) during the first year of therapy is frequent (15–20%), much more so toward reference products than biosimilars. The objectives of this study were to investigate the frequency and identify the potential predictors of switching between biosimilar and originator ESAs during the first year of treatment in patients with chronic kidney disease (CKD), or chemotherapy-related anemia from six large Italian geographic areas in the years 2009–2015.

Methods

A retrospective cohort study was conducted using six Italian regional claims databases (≥ 13 million inhabitants) during 2009–2015. Among incident epoetin users, the frequency of single, multiple, and backward switch during the first year of treatment was evaluated. Using frailty Cox models, potential predictors of first switch were identified. All analyses were stratified by the main indications for use.

Results

Among 102,240 incident epoetin users, 15,853 (15.5%) switched to another epoetin during the first year of therapy; only 18% of these switched to biosimilars. Single switch was more common (62.2% of the switchers) than multiple (23.5%) or backward switch (14.3%). In cancer, the cumulative number of transfusions and iron preparations dispensed, as well as hyperparathyroidism, were predictors of switching. In CKD, the cumulative number of transfusions, number of vitamin A/D preparations dispensed, and CKD severity increased the probability of switching.

Conclusions

Switching between ESAs was frequent in both CKD and cancer patients. The number of cumulative transfusions and severity of disease seemed to affect the switch.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Italian Association of Medical Oncology. Linee guida gestione della tossicità ematopoietica in oncologia. 2017. http://media.aiom.it/userfiles/files/doc/LG/2017_LGAIOM_Toss_ematopoietica.pdf. Accessed 2 Oct 2019.

  2. Aapro MS, Link H. September 2007 update on EORTC guidelines and anemia management with erythropoiesis-stimulating agents. Oncologist. 2008;13(Suppl 3):33–6.

    Article  CAS  Google Scholar 

  3. Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Somerfield MR, Temin S. American society of clinical oncology/american society of hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. J Oncol Pract. 2010;6(6):317–20.

    Article  Google Scholar 

  4. European Medicines Agency. European public assessment reports. http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Flanding%2Fepar_search.jsp&mid=WC0b01ac058001d124&searchTab=searchByAuthType&alreadyLoaded=true&isNewQuery=true&status=Authorised&status=Withdrawn&status=Suspended&status=Refused&keyword=Enter. Accessed 31 July 2019.

  5. Quintiles. The impact of biosimilar competition in Europe. Quintiles IMS. 2017. http://www.medicinesforeurope.com/wp-content/uploads/2017/05/IMS-Biosimilar-2017_V9.pdf. Accessed 2 Oct 2019.

  6. Dylst P, Vulto A, Simoens S. Barriers to the uptake of biosimilars and possible solutions: a Belgian case study. Pharmacoeconomics. 2014;32(7):681–91.

    Article  Google Scholar 

  7. Rompas S, Goss T, Amanuel S, Coutinho V, Lai Z, Antonini P, et al. Demonstrating value for biosimilars: a conceptual framework. Am Health Drug Benefits. 2015;8(3):129–39.

    PubMed  PubMed Central  Google Scholar 

  8. Trifirò G, Marcianò I, Ingrasciotta Y. Interchangeability of biosimilar and biological reference product: updated regulatory positions and pre- and post-marketing evidence. Expert Opin Biol Ther. 2018;18(3):309–15.

    Article  Google Scholar 

  9. European Medicines Agency (EMA). Biosimilars in the EU, Information guide for healthcare professionals. 2017. https://www.ema.europa.eu/en/documents/leaflet/biosimilars-eu-information-guide-healthcare-professionals_en.pdf. Accessed 2 Oct 2019.

  10. Agenzia Italiana del Farmaco (AIFA). Secondo position paper AIFA sui Farmaci Biosimilari. 2018.

  11. Agenzia Italiana del Farmaco (AIFA). L’uso dei farmaci in Italia. Rapporto Nazionale anno 2017. 2018. http://www.aifa.gov.it/sites/default/files/Rapporto_OsMed_2017_AIFA.pdf. Accessed 2 Oct 2019.

  12. Ingrasciotta Y, Giorgianni F, Bolcato J, Chinellato A, Pirolo R, Tari DU, et al. How much are biosimilars used in clinical practice? A retrospective Italian population-based study of erythropoiesis-stimulating agents in the years 2009–2013. BioDrugs. 2015;29(4):275–84.

    Article  Google Scholar 

  13. Food and Drug Administration. Considerations in demonstrating interchangeability with a reference product guidance for industry. 2017. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf. Accessed 2 Oct 2019.

  14. European Medicines Agency (EMA). Committee for Medicinal Products for Human Use (CHMP): guideline on similar biological medicinal products. 2014. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-rev1_en.pdf. Accessed 2 Oct 2019.

  15. Loiacono C, Sgroi C, Coppolino S, Cannata A, Ferrara R, Arcoraci V. How much are biosimilars used in Southern Italy? A retrospective analysis of epoetin utilization in the local health unit of Messina in the years 2010–2011. BioDrugs. 2012;26(2):113–20.

    Article  Google Scholar 

  16. D’Amore C, Da Cas R, Rossi M, Traversa G. Switching between epoetins: a practice in support of biosimilar use. BioDrugs. 2016;30(1):27–32.

    Article  Google Scholar 

  17. Locatelli F, Andrulli S, Memoli B, Maffei C, Del Vecchio L, Aterini S, et al. Nutritional-inflammation status and resistance to erythropoietin therapy in haemodialysis patients. Nephrol Dial Transplant. 2006;21(4):991–8.

    Article  CAS  Google Scholar 

  18. KDOQI, National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis. 2006;47(5 Suppl 3):S11–145.

    Google Scholar 

  19. Fine JP, Glidden DV, Lee KE. A simple estimator for a shared frailty regression model. J R Stat Soc Ser B Stat Methodol. 2003;65(1):317–29.

    Article  Google Scholar 

  20. Agenzia Italiana del Farmaco (AIFA). Position paper sui farmaci biosimilari (28/05/2013). http://www.agenziafarmaco.gov.it/sites/default/files/AIFA_POSITION_PAPER_FARMACI_BIOSIMILARI.pdf. Accessed 2 Oct 2019.

  21. Lonnemann G, Wrenger E. Biosimilar epoetin zeta in nephrology—a single-dialysis center experience. Clin Nephrol. 2011;75(1):59–62.

    CAS  PubMed  Google Scholar 

  22. Belleudi V, Trotta F, Addis A, et al. Italian Biosimilar Network (ItaBioNet). Effectiveness and safety of switching originator and biosimilar epoetins in patients with chronic kidney disease in a large-scale Italian cohort study. Drug Saf. 2019. https://doi.org/10.1007/s40264-019-00845-y.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Nagata S, Ikegaya N, Ogino S, Uchida S, Itaya M, Momita A, et al. The resection of thyroid cancer was associated with the resolution of hyporesponsiveness to an erythropoiesis-stimulating agent in a hemodialysis patient with aceruloplasminemia. Intern Med. 2017;56(7):805–10.

    Article  Google Scholar 

  24. Solomon SD, Uno H, Lewis EF, Eckardt K-U, Lin J, Burdmann EA, et al. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med. 2010;363(12):1146–55.

    Article  CAS  Google Scholar 

  25. Gilbertson DT, Ebben JP, Foley RN, Weinhandl ED, Bradbury BD, Collins AJ. Hemoglobin level variability: associations with mortality. Clin J Am Soc Nephrol. 2008;3(1):133–8.

    Article  CAS  Google Scholar 

  26. Grützmacher P, Ehmer B, Limbach J, Messinger D, Kulbe KD, Scigalla P. Treatment with recombinant human erythropoietin in patients with aluminum overload and hyperparathyroidism. Blood Purif. 1990;8(5):279–84.

    Article  Google Scholar 

  27. Ingrasciotta Y, Giorgianni F, Marcianò I, Bolcato J, Pirolo R, Chinellato A, et al. Comparative effectiveness of biosimilar, reference product and other erythropoiesis-stimulating agents (ESAs) still covered by patent in chronic kidney disease and cancer patients: an Italian population-based study. PLoS One. 2016;11(5):1–16.

    Article  Google Scholar 

  28. Marcianò I, Ingrasciotta Y, Giorgianni F, Bolcato J, Chinellato A, Pirolo R, et al. How did the introduction of biosimilar filgrastim influence the prescribing pattern of granulocyte colony-stimulating factors? Results from a multicentre, population-based study, from five Italian centres in the years 2009–2014. BioDrugs. 2016;30(4):295–306.

    Article  Google Scholar 

  29. Marcianò I, Ingrasciotta Y, Giorgianni F, et al. Pattern of use of biosimilar and originator somatropin in italy: a population-based multiple databases study during the years 2009–2014. Front Endocrinol (Lausanne). 2018;9:95.

    Article  Google Scholar 

  30. Bohlius J, Bohlke K, Castelli R, Djulbegovic B, Lustberg MB, Martino M, et al. Management of cancer-associated anemia with erythropoiesis-stimulating agents: ASCO/ASH clinical practice guideline update. J Clin Oncol. 2019;37(15):1336–51. https://doi.org/10.1200/JCO.18.02142.

    Article  CAS  PubMed  Google Scholar 

  31. Ministero della Salute, Agenzia Italiana del Farmaco (AIFA). Circolare AIFA del 3 agosto 2007. Linee guida per la classificazione e conduzione degli studi osservazionali sui farmaci. http://xoomer.virgilio.it/pgiuff/osservazionali.pdf. Accessed 14 Dec 2015.

Download references

Acknowledgements

Ylenia Ingrasciotta, Valentina Ientile, Alessandro Chinellato, Michele Tari, Giuseppe Roberto, Andrea Fontana, Maurizio Pastorello, Salvatore Scondotto, Pasquale Cananzi, Giuseppe Traversa, Marina Davoli, Francesco Trotta, Valeria Belleudi, Antonio Addis, Domenico Santoro, and Gianluca Trifirò are members of the I-BioNetwork. The authors thank Achille P. Caputi, Jenny Bolcato, Rosa Gini, Roberta Pirolo, Pastorello, Ilaria Uomo, Sebastiano W. Pollina Addario, Roberto Da Cas, Mariangela Rossi, and Armando Genazzani, who are also members of the I-BioNetwork.

Author information

Authors and Affiliations

  1. Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy

    Ylenia Ingrasciotta, Valentina Ientile & Gianluca Trifirò

  2. Department of Epidemiology, Lazio Regional Health Service, Rome, Italy

    Valeria Belleudi, Antonio Addis & Marina Davoli

  3. Italian Medicines Agency, Rome, Italy

    Francesco Trotta

  4. Unit of Biostatistics, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy

    Andrea Fontana

  5. Pharmaceutical Service, Local Health Authority (ULSS9), Treviso, Italy

    Alessandro Chinellato

  6. Caserta-1 Local Health Service, Caserta, Italy

    Daniele Ugo Tari

  7. Epidemiology Unit, Regional Agency for Healthcare Services of Tuscany, Florence, Italy

    Giuseppe Roberto

  8. Department of Pharmacy, Palermo Local Health Unit, Palermo, Italy

    Maurizio Pastorello

  9. Department of Epidemiologic Observatory, Health Department of Sicily, Palermo, Italy

    Salvatore Scondotto

  10. Sicilian Regional Centre of Pharmacovigilance, Servizio 7-Farmaceutica, Health Department of Sicily, Palermo, Italy

    Pasquale Cananzi

  11. Pharmacoepidemiology Unit, National Centre for Epidemiology, Italian National Institute of Health, Rome, Italy

    Giuseppe Traversa

  12. Health-Unit for Pharmaceutical Governance, Umbria Region, Perugia, Italy

    Mariangela Rossi

  13. Unit of Clinical Pharmacology, A.O.U. Policlinico “G. Martino”, Messina, Italy

    Gianluca Trifirò

Authors
  1. Ylenia Ingrasciotta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valeria Belleudi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesco Trotta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Antonio Addis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andrea Fontana
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alessandro Chinellato
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Valentina Ientile
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Daniele Ugo Tari
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Giuseppe Roberto
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Maurizio Pastorello
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Salvatore Scondotto
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Pasquale Cananzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Giuseppe Traversa
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Marina Davoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Mariangela Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Gianluca Trifirò
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

On behalf of the Italian Biosimilars Network (I-BioNetwork)

  • Achille P. Caputi
  • , Jenny Bolcato
  • , Roberta Pirolo
  • , Rosa Gini
  • , Armando A. Genazzani
  • , Ilaria Uomo
  • , Sebastiano W. Pollina Addario
  •  & Roberto Da Cas

Contributions

GTri, YI, VB, FT, and AA generated the study idea. YI wrote the final manuscript. VI, AF, and YI performed the data analysis. MR, VB, AC, GR, MP, SS, and GTra extracted the data and authorized their utilization. DS, GTri, and YI assisted in interpreting the results from a clinical perspective. All authors assisted interpretation of the results and manuscript revision and read and approved the final manuscript.

Corresponding author

Correspondence to Ylenia Ingrasciotta.

Ethics declarations

Funding

This study was conducted in the context of the finalized research project “Assessment of Short and Long Term Risk–Benefit Profile of Biologics through Healthcare Database Network in Italy” (RF-2010-2320172), which was funded by the Italian Health Ministry. The financial assistance was used to access and analyze data from different partners.

Conflict of interest

Gianluca Trifirò declares his participation in advisory boards on biosimilars, organized by Sandoz and Hospira; furthermore, he coordinates a pharmacoepidemiology research team at the University of Messina, which receives research grants for projects that are not related to the topic of the paper. Ylenia Ingrasciotta, Valeria Belleudi, Francesco Trotta, Antonio Addis, Andrea Fontana, Alessandro Chinellato, Valentina Ientile, Daniele Ugo Tari, Giuseppe Roberto, Maurizio Pastorello, Salvatore Scondotto, Pasquale Cananzi, Giuseppe Traversa, Marina Davoli, and Mariangela Rossi declare that they have no conflicts of interest that might be relevant to the contents of this study.

Ethical approval

This study was conducted in the context of the “Assessment of Short and Long Term Risk–Benefit Profile of Biologics through Healthcare Database Network in Italy” project, funded by the Italian Ministry of Health. The study protocol was notified to the Ethical Committee of the Academic Hospital of Messina [31], according to the current national law. The manuscript does not contain clinical studies or patient data. For this type of study formal consent is not required.

Additional information

The members of the Italian Biosimilars Network (I-BioNetwork) are listed in the acknowledgements section.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ingrasciotta, Y., Belleudi, V., Trotta, F. et al. In Search of Predictors of Switching Between Erythropoiesis-Stimulating Agents in Clinical Practice: A Multi-Regional Cohort Study. BioDrugs 34, 55–64 (2020). https://doi.org/10.1007/s40259-019-00385-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40259-019-00385-y

Search

Navigation