Market access for biopharmaceuticals and biosimilars: a case study

Biosimilares/Investigación | Posted 26/11/2010 post-comment0 Post your comment

Filgrastim is one of the first biopharmaceuticals for which biosimilars have entered the market. This case study illustrates the health economic challenges and the issues that arose in the R & D, registration, pricing and reimbursement of the biopharmaceutical and its biosimilars [1].


The treatment of cancer with cytotoxic agents used for chemotherapy may cause neutropenia (a below normal count of neutrophils or white blood cells) or febrile neutropenia (fever and neutropenia) through damage or destruction of bone marrow. Neutropenia is associated with gastrointestinal and pulmonary infections as well as sepsis, and may lead to a postponement or dose reduction of subsequent chemotherapy cycles. Granulocyte colony-stimulating factors, such as filgrastim and pegfilgrastim, have been shown to be effective in accelerating the recovery of neutrophils and in preventing neutropenia.

Filgrastim, the reference biopharmaceutical, has been marketed under the name Neupogen since 1991. It is licensed for reducing the duration of neutropenia and the incidence of febrile neutropenia in patients undergoing myelosuppressive chemotherapy for malignant diseases and for reducing the duration of neutropenia in patients undergoing myeloablative therapy followed by bone marrow transplantation, who are at risk of prolonged severe neutropenia. It is also used to mobilise peripheral blood stem cells, to treat severe congenital, cyclical or idiopathic neutropenia, or neutropenia associated with advanced HIV infection.

Although Neupogen is reimbursed for its licensed indications in many countries, economic evaluations have provided conflicting results on its cost-effectiveness in prophylaxis of chemotherapy-induced neutropenia in patients with cancer. The most important cost drivers are filgrastim costs and hospital accommodation costs. The cost-effectiveness depends on whether the high cost of filgrastim is offset by the reduced incidence of febrile neutropenia and a shorter hospital stay.

Five filgrastim biosimilars have been developed to date: the EMA registered Biograstim, Filgrastim Ratiopharm, Ratiograstim and TevaGrastim in 2008 and Filgrastim Sandoz in 2009 for the same indications as the reference Neupogen. These biosimilars were approved because they were deemed to have a similar, but not identical, quality, safety and efficacy profile to the filgrastim biopharmaceutical. For example, Filgrastim Ratiopharm differs from the reference biopharmaceutical in terms of pH and the concentration of filgrastim and of polysorbate 80. The characteristics of the two active substances, however, were found to be comparable.

Five clinical studies were conducted to demonstrate equivalent clinical pharmacology in two phase I trials, and efficacy and safety in three phase III studies. The biosimilar was compared to Neupogen and placebo in the main study involving 348 patients with breast cancer and was found to be similar with regard to duration of severe neutropenia and the incidence of febrile neutropenia.

A long-acting, pegylated form of filgrastim, pegfilgrastim, was registered by the EMA in 2002 and is marketed under the name Neulasta. Randomised clinical trials have established non-inferiority of pegfilgrastim compared to Neupogen. Recently, three US economic evaluations of pegfilgrastim have been published [2–4]. A cost-utility analysis in adult cancer patients receiving chemotherapy compared three treatment alternatives: primary prophylaxis with pegfilgrastim, primary prophylaxis with the original filgrastim and no prophylaxis [2]. Indirect medical costs, productivity costs, probabilities and utilities from the literature, and data on direct medical costs from a claims database of 115 medical centres were considered. The findings gave pegfilgrastim the best profile: treatment with pegfilgrastim was more effective and less expensive than the comparators. A univariate sensitivity analysis supported the dominance of pegfilgrastim even if the price of original filgrastim had been 26% lower.

A second economic evaluation calculated the incremental cost-effectiveness and cost-utility ratios of primary prophylaxis with pegfilgrastim compared with filgrastim used for six days in patients with aggressive non-Hodgkin’s lymphoma receiving myelosuppressive chemotherapy [3]. Doing a different calculation, and taking into account the benefit of optimising chemotherapy, primary prophylaxis with pegfilgrastim has an incremental cost-effectiveness ratio (ICER) of Euros 1,150 per life-year gained or Euros 1,300 per quality-adjusted life-year gained compared with filgrastim. These results were sensitive to changes in the unit cost of filgrastim and pegfilgrastim, and the relative risk of febrile neutropenia between pegfilgrastim and filgrastim.

A third economic evaluation compared primary versus secondary prophylaxis with pegfilgrastim in women with early-stage breast cancer receiving myelosuppressive chemotherapy with a risk of febrile neutropenia of approximately 20% or higher [4]. Working in a similar way to study 3, researchers found that primary prophylaxis with pegfilgrastim has an ICER of Euros 85,000 per life-year gained or Euros 89,000 per quality-adjusted life-year gained compared with secondary prophylaxis. The authors stated that the cost-effectiveness of primary prophylaxis with pegfilgrastim was less cost-effective than many other healthcare interventions, but compared favourably with other supportive care therapies in cancer. The analysis was limited to pegfilgrastim and did not consider Neupogen or biosimilars. However, the authors argued that using Neupogen should be similar or less cost effective than using Neulasta (Amgen) because it is more expensive and less effective in reducing febrile neutropenia rates. They recommended that the costs and effects of filgrastim biosimilars be compared with those of pegfilgrastim.


It is difficult to prove that biopharmaceuticals are cost effective because they are expensive.

The case study showed that: (a) the cost-effectiveness of the filgrastim biopharmaceutical has not been clearly established, (b) the filgrastim biosimilars are similar, but not identical to the filgrastim biopharmaceutical, and (c) the pegfilgrastim biopharmaceutical is likely to be cost-effective compared to the filgrastim biopharmaceutical (although its cost-effectiveness compared to the filgrastim biosimilars still needs to be determined).

Related articles

The case for health economic studies on biopharmaceuticals

Biopharmaceuticals: the start of personalised medicine

Health economic challenges for biosimilars


1. Simoens S. Health economics of market access for biopharmaceuticals and biosimilars. J Med Econ. 2009;12(3):211–8.

2. Eldar-Lissai A,Cosler, LE, Culakova E, Lyman GH. Economic analysis of prophylactic pegfilgrastim in adult cancer patients receiving chemotherapy. Value Health. 2008;11(2):172–9.

3. Lyman G, Lalla A, Barron R, Dubais RW. Cost-effectiveness of pegfilgrastim versus 6-day filgrastim primary prophylaxis in patients with non-Hodgkin’s lymphoma receiving CHOP-21 in United States. Curr Med Res Opin. 2009;25(2):401–11.

4. Ramsey SD, Liu Z, Boer R, Sullivan SD, Malin J, Doan QV et al. Cost-effectiveness of primary versus secondary prophylaxis with pegfilgrastim in women with early-stage breast cancer receiving chemotherapy. Value Health. 2009;12(2):217–25.

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