A review of biosimilar agents in oncology/haematology

August 18, 2011 8:12 AM

Two German scientists, Diether Niederwieser and Stephan Schmitz have recently published a review article summarising the experiences with biosimilars launched in the EU in oncology/haematology setting.

After giving some information about the regulations in the EU, US and also mentioning the position of WHO, the writers reviewed the two group of biosimilar products which was introduced in the EU.

In oncology/haematology setting, currently two different group of products are approved as biosimilars. Erythropoesis-stimulating agents (ESAs) up-regulate red blood cell production and are indicated for the treatment of symptomatic anemia in adult cancer patients with non-myeloid malignancies receiving chemotherapy.

As ESAs are among the most widely used biologics, two biosimilar epoetins were the first “oncology” biosimilars to receive European marketing approval following the EU guidelines.

After ESAs, granulocyte colony-stimulating factor (G-CSF) filgrastim biosimilars are approved in the EU. XM02 of Teva and Ratiofarm was the first filgrastim biosimilars in the EU. Following XM02, EP2006 of Sandoz (and Hexal) was approved and lately PLD108 of Hospira is approved .

Filgrastim is a widely used biologic, over 7.7 million patients have been exposed to the innovator product Neupogen of Amgen. In the EU, filgrastim is approved for usage in adults and children to shorten the duration of neutropenia and reduce the incidence of febrile neutropenia following receipt of cytotoxic chemotherapy.

It is also used to aid delivery of chemotherapy to maintain dose intensity and to support dose-dense chemotherapy. Filgrastim is also indicated to mobilise peripheral blood progenitor cells (PBPC) in both cancer patients and healthy donors and to support engraftment and neutrophil recovery after stem cell transplantation. Outside the oncology setting, filgrastim is indicated for the treatment of severe chronic neutropenia and to maintain neutrophil counts or reverse neutropenia in patients infected with human immunodeficiency virus.

The use of biosimilars in oncology setting is important because they are not used simply for the replacement of hormones (e.g. growth hormones, insulin) or the treatment of renal insufficiency (i.e. erythropoetin); but as supportive therapy for the immunosuppressed patients receiving multiple cycles of cytotoxic chemotherapy, or for healthy stem cell donors who obtain no direct therapeutic benefit from the treatment.

Extrapolation of indications
Extrapolation involves the approval of a drug for indications for which it has not been evaluated in clinical trials. For the filgrastim biosimilars XM02, EP2006 and PLD108, extrapolation from data in healthy adults and CIN has allowed approval in all indications of the reference product.

Extrapolation of indications is fully compliant with the current guidelines but this issue has raised some concerns. Even in the European Public Assessment Reports (EPARs) for XM02, PBPC mobilisation was highlighted by the EMA as an ‘area of uncertainty’, because it is not known whether efficacy in CIN can be fully extrapolated to PBPC mobilisation.

Substitution of one product with another that has the same INN, by the pharmacist, is common practice with generic drugs. As a consequence of their complexity, automatic substitution of biologics could give rise to different clinical consequences and should be ruled out for reasons of patient safety the writers say. If  you want to read more information about this topic, you can check our post about interchangeability here.

Biosimilar ESAs and G-CSFs have distinct brand names in the EU. The summary of product characteristics (SmPC) for biosimilar epoetin alfa and epoetin zeta include data from the reference product Eprex SmPC; no biosimilar data are provided and it is not clear that the product being described is a biosimilar.

The SmPC for the biosimilar filgrastim products XM02, EP2006, and PLD108 present data from the SmPC of the reference product Neupogen. Comparability studies to a ‘reference product’ are mentioned; however, biosimilar data are not presented and extrapolated indications are not identified as such.

Safety and immunogenicity
Immunogenicity is the most important safety issue concerning all biosimilar products. In oncology? haematology, biosimilar ESAs have additional postmarketing studies in their risk-management plan to address safety concerns such as pure red cell aplasia, thrombotic vascular events and tumour growth potential.

In contrast, the postmarketing program for biosimilar G-CSFs differs between products. Routine risk management and a signal detection procedure for immunologic events are proposed for the biosimilar filgrastim XM02, although this is the first product for which extrapolated indications were granted. For the biosimilar filgrastim EP2006, a more extensive postmarketing program is described, including a phase IV study, and cooperation with the severe chronic neutropenia registry, as well as aphaeresis centres to investigate its use for mobilisation in healthy stem cell donors. Some safety and potential immunogenicity differences between the biosimilar filgrastim PLD108 and its reference product (Neupogen)  were reported in the product EPAR.

In the United Kingdom, the Medicines and Healthcare products Regulatory Agency have marked the biosimilar ESA products epoetin alfa and epoetin zeta, and the biosimilar filgrastim products XM02, EP2006 and PLD-108 with a black triangle, which indicates these products should be intensively monitored in order to confirm their risk ? benefit profile. It should be noted that this scheme is not limited to biologics, but applies to all new medicinal products for which limited safety data raises concerns.

Summary and result

According to the article, it is clear that writers choose to be on the cautious side while using biosimilars in the oncology setting. They mentioned about the differences, possible problems and also the deficiencies of the approvals of biosimilars in Europe.

What do you think? Do you have any opinion to share with us? Please comment below to contribute…

Source: Niederwieser D Biosimilar agents in oncology/haematology: from approval to practice. Eur  J Haematol. 2011; 86:277-88.

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