Health economics of market access for biopharmaceuticals and biosimilars

Abstract

Background and scope: This article discusses health economic challenges of research and development, registration, pricing and reimbursement of biopharmaceuticals and biosimilars. A literature search was carried out of PubMed, Centre for Reviews and Dissemination databases, Cochrane Database of Systematic Reviews and EconLit up to March 2009.

Findings: The development process of biopharmaceuticals is risky, lengthy, complex and expensive. Registration is complicated by the inherent variation between biopharmaceuticals. Also, as biopharmaceuticals are likely to be efficacious in a subgroup of the patient population, there is a need to select the most responsive target population and to identify biomarkers. To inform pricing and reimbursement decisions, the development process needs to collect comparative data to calculate the incremental cost effectiveness and budget impact of biopharmaceuticals. There is a role for innovative mechanisms such as risk-sharing arrangements to reimburse biopharmaceuticals.

Conclusions: Given that biosimilars are similar, but not identical to the reference biopharmaceutical, the development process needs to generate clinical trial data in order to gain marketing authorisation. From a health economic perspective, the question arises whether inherent differences between biopharmaceuticals and biosimilars produce differences in safety, effectiveness and costs: to date, this question is unresolved. The early inclusion of health economics in the process of developing biopharmaceuticals and biosimilars is imperative with a view to demonstrating their relative (cost) effectiveness and informing registration, pricing and reimbursement decisions.

Key words::

• biopharmaceutical
• biosimilar
• health economics
• pricing
• registration
• reimbursement
• research and development

Introduction

The US Food and Drug Administration (FDA) defines biotechnology as the collection of industrial processes that involve the use of biological systems (e.g., bacteria, yeast, human cells) to identify, sequence and manipulate DNA aimed at producing therapeutic and medical diagnostic products¹. Biopharmaceutical medicines are reference or originator medicinal products made by or derived from living organisms using biotechnology² (see Figure 1). Biopharmaceuticals tend to have a large size and a complex structure, and are manufactured from a unique line of living cells, making it impossible to ensure an identical copy. This is in contrast with conventional chemical medicines, which tend to have a small size and simple structure, and are manufactured using a predictable chemical process that generates identical copies.

There is a need to assess the health economic challenges in gaining market access for biopharmaceuticals. Biopharmaceuticals represent a fast-growing segment of the pharmaceutical market, making up one third of products in the development pipeline and accounting for 9% of pharmaceutical expenditure³. Whereas the first generation of biopharmaceuticals tended to consist of first-in-class products addressing unmet clinical needs in small populations (e.g., bevacizumab for metastatic colorectal cancer), the current wave of products target larger populations in the presence of competitor medicines (e.g., insulins for type 2 diabetes mellitus)⁴. The biopharmaceutical market is expected to grow by 12–15% per year⁵, as a result of a burgeoning pipeline, approval for more common conditions, increased utilisation and expanding indications⁶. In addition, there is a mounting pressure from patients' groups to increase access to biopharmaceuticals. On the one hand, biopharmaceuticals may help to sustain the financial bottom-line of pharmaceutical companies as they tend to be efficacious at often high prices⁷; on the other hand, biopharmaceuticals may be viewed by regulatory authorities, third-party payers and patients as being expensive and having limited outcome data at launch.

There is a need to assess the health economic challenges in gaining market access for biosimilars. When the 20-year patent on a biopharmaceutical expires, less expensive versions of the medicine, so-called biosimilar medicines or follow-on biologics, can enter the market (see Figure 1). Biosimilars are cheaper than the reference biopharmaceuticals due to lower costs of research and development⁸. It has been estimated that a 20% price reduction of five off-patent biopharmaceuticals as a result of biosimilar competition would save the European Union over 1.6 billion Euro per year⁹. However, biosimilars are new biopharmaceutical products that are similar, but knot identical to the reference biopharmaceutical.

A health economic approach to market access for biopharmaceuticals and biosimilars serves to aid researchers and decision makers in pharmaceutical companies and government to identify those products in the development process that are likely to be safe, effective and cost effective, and to guide the rationale for making registration, pricing and reimbursement decisions. A health economic approach can support the implementation of safe and (cost) effective health technologies that support further health improvements, while containing health expenditure. This article aims to conduct a literature review of the health economics of market access for biopharmaceuticals and biosimilars among researchers and decision makers by focusing on the research and development, registration, pricing and reimbursement of biopharmaceuticals and biosimilars.

Methods

Relevant studies were identified by searching PubMed, Centre for Reviews and Dissemination databases (Database of Abstracts of Reviews of Effects, National Health Service Economic Evaluation Database, and Health Technology Assessments Database), Cochrane Database of Systematic Reviews, and EconLit up to March 2009. Additionally, the bibliography of included studies was checked for other relevant studies. Search terms included ‘biotechnology’, ‘biopharmaceutical’, ‘biosimilar’, ‘follow-on biologic’, ‘market access’, ‘research and development’, ‘registration’, ‘pricing’, ‘reimbursement’, ‘health economics’, ‘pharmaco-economics’, ‘economic evaluation’ alone and in combination with each other.

Biopharmaceuticals

The class of biopharmaceuticals has been available for over 20 years and includes blood coagulation modulators, enzymes, erythropoietins, gonadotrophins, granulocyte colony-stimulating factors, human growth hormones, human insulins, interferons, interleukins, monoclonal antibodies, tissue plasminogen activators, and vaccines (see Table 1).

Research and development

Several economic studies have documented that research and development of biopharmaceuticals is risky, lengthy, complex, and expensive. An analysis of the success rate of medicines found that biopharmaceuticals had a higher overall success rate than chemically-derived medicines (30 vs. 21.5%)¹⁰, but had an inferior success rate in phase III trials¹¹. This implies that biopharmaceuticals have a higher probability of failure at a stage where high development costs have already been incurred. The average development time from initiation of phase I trials to marketing authorisation by the US FDA amounted to 97.7 months for biopharmaceuticals as compared to 90.3 months for chemically-derived medicines¹⁰. Furthermore, development times have increased over time given that the development process moves to more complicated target biopharmaceuticals¹². Two analyses found similar costs of research and development for biopharmaceuticals and chemically-derived medicines, although the cost drivers differed^10,13. Biopharmaceuticals incurred higher costs of manufacturing processes, had a lower success rate in the more expensive phase III trials, and experienced a longer development time. Finally, a recent US study showed that, in order to break even on research and development costs, a data exclusivity period of between 12.9 and 16.2 years should be granted to innovator companies of biopharmaceuticals before a competitor can submit an application for the marketing authorisation of a biosimilar based on the data of the biopharmaceutical¹².

Registration

In Europe, the European Medicines Agency (EMEA) assesses the quality, safety and efficacy of biopharmaceuticals through the centralised procedure¹⁴. In this respect, a number of issues specific to biopharmaceuticals need to be considered.

There is inherent variation between biopharmaceuticals because they are derived from living organisms. Indeed, biopharmaceuticals may vary in terms of shape of the molecule, the type and length of any sugar or carbohydrate groups that may be attached to the molecule. Biopharmaceuticals require multifaceted manufacturing processes and changes to the manufacturing process can result in differences in quality, safety and efficacy⁸. As a result, biopharmaceuticals differ within a batch, from batch to batch, and between companies producing the same biopharmaceutical¹⁵.

Biopharmaceuticals typically bind to their biological target (e.g., a protein linked to a disease). Therefore, a biopharmaceutical is likely to be particularly efficacious in a specific subgroup of the patient population. For instance, trastuzumab is a monoclonal antibody that binds to the human epidermal growth factor receptor 2 (HER2) protein and has been shown to be efficacious in the treatment of patients with metastatic breast cancer whose tumours over-express HER2¹⁶. This has implications for the clinical development of biopharmaceuticals in that it highlights the need to select the most responsive target population, to collect information on relevant patient characteristics, and to identify suitable biomarkers¹⁷. It could be argued that, in this respect, biopharmaceuticals involve a paradigm shift towards personalised medicine.

Limited data about safety risks tend to be available at the time of the marketing authorisation by EMEA. Therefore, possible concerns about adverse events after long treatment periods can be addressed through pharmacovigilance studies after authorisation and, if appropriate, through post-authorisation safety studies. For instance, infliximab was approved for the treatment of ankylosing spondylitis in 2003 subject to the condition that a follow-up clinical study was undertaken to investigate the safety and efficacy of infliximab over a period of 2 years¹⁸. Also, a risk management plan must be submitted to EMEA detailing the actions and the surveillance that is undertaken to identify and manage potential safety risks. For instance, to minimise the risk of infections following administration of natalizumab for relapsing multiple sclerosis, the risk management plan imposed a clear-cut definition of the target population, the requirement for established multiple sclerosis, an escape rule for non-responders, the administration in specialised centres by experienced physicians only, clear contraindications, a patient alert card, and an educational programme for physicians¹⁹. Finally, EMEA has launched a public consultation on draft guidelines relating to the post-authorisation follow-up of effectiveness, adverse reactions and risk management of advanced therapy medicinal products, including biopharmaceuticals²⁰.

Pricing and reimbursement

A comparative analysis measured ex-manufacturer prices of biopharmaceuticals in five European countries (France, Germany, Italy, Spain and the UK), Australia, Canada, Japan, Mexico and the US²¹. The data originated from the IMS Health MIDAS database for 2005. Prices were converted using gross domestic product purchasing power parities. The results indicated that all countries tended to have higher biopharmaceutical prices than the US. The authors argued that biopharmaceutical prices may be less regulated than those of chemically-derived medicines given that: (a) some countries exclude biopharmaceuticals used in hospital from price regulation, (b) price comparisons with other products in a therapeutic class are less likely to occur for biopharmaceuticals with a novel mechanism of action or indication, (c) informal cost-effectiveness thresholds may be higher for biopharmaceuticals that address unmet clinical needs or that treat orphan diseases, and (d) some countries have in place industrial policies to support the development of biopharmaceuticals.

In order to inform pricing and/or reimbursement decisions, an increasing number of countries require pharmaceutical companies to carry out an economic evaluation with a view to demonstrating the value of a new biopharmaceutical and to conduct a budget impact analysis with a view to exploring the affordability of a biopharmaceutical²². Therefore, it is the author's opinion that the early inclusion of health economics in the process of developing a biopharmaceutical is imperative and that there is a need for a value-based approach to pipeline decision making. Reimbursement may not only depend on the value for money of the biopharmaceutical at the time of the reimbursement application, but also on its value after a number of years following the admission to the reimbursement system. Therefore, pharmaceutical companies need to explore setting up databases or observational studies to demonstrate the post-launch cost effectiveness of a biopharmaceutical based on phase IV trials.

With a view to assessing the cost effectiveness of biopharmaceuticals, regulatory authorities tend to demand data on the effectiveness of biopharmaceuticals in a real-world setting rather than on their efficacy in a structured setting²³. Also, as the cost effectiveness of a biopharmaceutical is calculated relative to a relevant comparator, there is a need for comparative data. Both factors have implications for the design of clinical trials. For biopharmaceuticals that provide a first-in-class therapy for unmet clinical needs, the incremental cost effectiveness can be calculated on the basis of clinical trials comparing the biopharmaceutical with placebo. For biopharmaceuticals that are marketed in the presence of competitor medicines, there is a need to compute the incremental cost effectiveness based on head-to-head trials of the biopharmaceutical relative to a relevant comparator⁴.

The cost effectiveness and budget impact of biopharmaceuticals are likely to be inhibited by their high prices. The selection of a specific target population may improve the cost effectiveness and reduce the budget impact of biopharmaceuticals. For instance, despite the high price of trastuzumab of around US$19,000 per year, the UK National Institute for Health and Clinical Excellence (NICE) found trastuzumab to be cost effective in the subgroup of patients with metastatic breast cancer whose tumours over-express HER2 as indicated by a diagnostic test²⁴.

Innovative mechanisms have been proposed for the reimbursement of biopharmaceuticals. Risk-sharing arrangements are schemes in which the pharmaceutical company shares the risk with the third-party payer that the product may not be effective for a particular patient. If the product does not have the expected effect, the company may loose some or all product revenue, or needs to provide a replacement product²⁵. Such arrangements are instituted at the level of a defined patient population rather than a group of patients cared for by an individual institution or healthcare provider, and may require physicians to be trained in the appropriate use of the biopharmaceutical, and necessitate the implementation of a tracking system to follow up its use. With respect to biopharmaceuticals, for instance, NICE denied reimbursement for a number of drug classes treating multiple sclerosis (including beta interferons) in the UK in 2002 given that they were considered to be expensive and not cost effective. Under a risk-sharing arrangement, pharmaceutical companies reduced prices if their medicines did not attain a target level of effectiveness in the patient population²⁶. However, it should be noted that the creation of such arrangements at the time of market access may be inhibited by a lack of data on the costs and effects of the biopharmaceutical in the real-world setting.

Biosimilars

In Europe, the first patents on biopharmaceuticals expired in 2001 and the first biosimilars were approved by EMEA in April 2006. To date, biosimilars of somatropin, epoetin alfa and epoetin zeta have entered the European market (see Table 1). In the coming years, patents will expire on some major biopharmaceuticals, such as interferons, insulins and granulocyte-colony stimulating factors. This is likely to lead to the market entry of a number of biosimilars in the not too distant future.

Research and development

Biosimilars are agents that are similar, but not identical to the reference biopharmaceutical. Therefore, the research and development process needs to generate clinical trial data in order to gain marketing authorisation. Indeed, to substantiate the claim of biosimilarity in Europe, the manufacturer must conduct a direct and extensive comparability exercise between the biosimilar and the reference biopharmaceutical, with a view to demonstrating that the two products have similar quality, safety and efficacy. Although there is no need to repeat all trials of the reference biopharmaceutical, the need to conduct some biosimilar trials enrolling several hundreds of patients involves considerable expense and time. A US study has estimated that the costs of biosimilar trials would range from US$10 to 40 million²⁷. This study also reported that the required investment in manufacturing processes, which often needs to be initiated during the research and development process, would amount to US$250–450 million. Both factors raise market entry costs of biosimilars.

Registration

In Europe, a regulatory framework exists for EMEA to assess the application for marketing authorisation of biosimilars²⁸. In light of the variation between biopharmaceuticals, the approval process is specific to each product. In general, a biosimilar is registered if it is similar to the reference biopharmaceutical in terms of safety, quality and efficacy. Dossiers of biosimilars tend to include data on clinical trials with a view to demonstrating similar safety and efficacy with the reference biopharmaceutical. In other words, a similar therapeutic performance of the biosimilar and the reference biopharmaceutical can be assumed. EMEA guidelines also impose pharmacovigilance programmes to follow up safety and efficacy of biosimilars once approval has been gained.

To date, there is no defined regulatory pathway for the FDA to review or approve biosimilars in the US, although several bills to set up such a pathway have been introduced in Congress this year. No consensus has been reached on a number of registration issues. For instance, a biopharmaceutical is not guaranteed to benefit from a 20-year patent protection due to the possibility of patent litigation. This issue also applies to biosimilars: given that biosimilars are different from biopharmaceuticals, the question can be asked whether the patent of the biopharmaceutical is enforceable. Another major registration issue relates to the duration of the data exclusivity period, i.e. the period of time during which the application for a biosimilar cannot refer to the documentation of the reference biopharmaceutical. Nevertheless, if a biosimilar registration pathway would be in place in the US by 2010, this could be expected to pave the way for the market entry of biosimilars from 2013.

Pricing and reimbursement

EMEA guidelines recognise that there may be differences between biosimilars from different manufacturers or when compared with the reference biopharmaceutical²⁸. From a health economic perspective, the question arises whether inherent differences between biopharmaceuticals and biosimilars produce differences in safety, effectiveness and costs. To date, this question is unresolved. If the biosimilar and the reference biopharmaceutical are interchangeable, generic substitution will maintain effectiveness at reduced costs, and can be recommended. If the biosimilar and the reference biopharmaceutical are not interchangeable, the savings arising from less expensive biosimilars need to be weighed against the impact on effectiveness and costs of therapy: a lower effectiveness of a biosimilar may result in the need for additional therapy or hospitalisation and may entail that the patient needs to take more time off work. In this case, an economic evaluation needs to be performed to assess the value of the biosimilar.

An economic evaluation calculates the incremental cost-effectiveness ratio of an intervention relative to a relevant comparator. If the comparator encompasses a biopharmaceutical and a biosimilar, the price of which medicine should be used to value costs? This choice is likely to have an impact on the cost effectiveness of the intervention.

Many countries have developed guidelines that serve as a standard for designing and conducting economic evaluations to be included in medicine reimbursement applications²⁹. No guidelines specify whether the valuation of comparator costs should be based on the price of the reference biopharmaceutical or the biosimilar. However, Belgian guidelines do state that, if the comparator covers two kinds of medicines with a different price, but equal outcomes, the least expensive medicine should be used in the economic evaluation because such a medicine is more cost effective than the more expensive medicine³⁰. This would imply that, if there are no differences in effectiveness between the biopharmaceutical and the biosimilar, the price of the biosimilar needs to be used in the economic evaluation, even if biosimilars are not frequently used in Belgium.

Guideline recommendations about the choice of comparator may also inform this debate. Countries such as the Baltic countries, Finland, France, Italy, Spain and Sweden recommend that the most common treatment should be used as comparator²⁹. If the most common treatment is a medicine, this implies that the choice of comparator and the price to value costs of the comparator depend on the market share of the reference biopharmaceutical and the biosimilar.

Case study

The previous sections have outlined the health economics of market access for biopharmaceuticals and biosimilars. To illustrate these health economic challenges, the issues that arose in the research and development, registration, pricing and reimbursement of the biopharmaceutical filgrastim and the filgrastim biosimilars are described in this section. This case study was selected because filgrastim is one of the first biopharmaceuticals for which biosimilars have entered the market since 2008.

The treatment of cancer with cytotoxic agents used for chemotherapy may cause neutropenia (i.e., a below normal count of neutrophils or white blood cells) or febrile neutropenia (i.e., 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 cycles³¹. 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^32,33.

Filgrastim, the reference biopharmaceutical, has been marketed under the name Neupogen (Amgen) since 1991. The filgrastim biopharmaceutical has been 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 and 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 human immunodeficiency virus infection³⁴.

Although the filgrastim biopharmaceutical is reimbursed for its licensed indications in many countries, economic evaluations have provided conflicting results on the cost effectiveness of the filgrastim biopharmaceutical as prophylactic therapy of chemotherapy-induced neutropenia in patients with cancer. Also, this case study illustrates that the cost effectiveness of biopharmaceuticals may be inhibited by their high prices: economic evaluations of the filgrastim biopharmaceutical showed that the most important cost drivers were filgrastim costs and hospital accommodation costs. The cost effectiveness depended on whether the higher costs of filgrastim were offset by the reduced incidence of febrile neutropenia and shorter hospital stay. A literature review observed cost savings of primary prophylaxis with filgrastim in six out of 14 economic evaluations, cost savings of secondary prophylaxis as compared with primary prophylaxis in two evaluations, cost savings of prophylaxis in patients undergoing bone marrow transplantation in six out of seven evaluations, and cost savings of prophylaxis in patients undergoing peripheral blood stem cell transplantation in four out of seven evaluations³⁵.

Five filgrastim biosimilars have been developed to date: EMEA registered Biograstim (CT Arzneimittel), Filgrastim Ratiopharm (Ratiopharm), Ratiograstim (Ratiopharm), and TevaGrastim (Teva) in 2008 and Filgrastim Sandoz (Sandoz)⁵. Five in 2009 for the same indications as the reference filgrastim biopharmaceutical. These biosimilars were approved because they were deemed to have a similar, but not identical quality, safety and efficacy profile to the filgrastim biopharmaceutical. Take the example of Filgrastim Ratiopharm. Although this biosimilar differs from the filgrastim biopharmaceutical in terms of pH and the concentration of filgrastim and of polysorbate 80, the characteristics of the two active substances were found to be comparable. The biosimilar applicant had to undertake extensive characterisation studies to show biosimilarity between the two products. Furthermore, five clinical studies were conducted to demonstrate equivalent clinical pharmacology in two phase I trials, efficacy and safety in three phase III studies. The biosimilar was compared to the filgrastim biopharmaceutical and to placebo in the main study involving 348 patients with breast cancer. No relevant differences were found between the biosimilar and the filgrastim biopharmaceutical with regard to duration of severe neutropenia or the incidence of febrile neutropenia. Finally, the risk management plan of the biosimilar involved a commitment from the applicant to investigate post-marketing adverse events for immunogenicity³⁶.

A long-acting, pegylated form of filgrastim, pegfilgrastim, was registered by EMEA in 2002 and is marketed under the name Neulasta (Amgen). Randomised clinical trials have shown that pegfilgrastim is at least as effective as the filgrastim biopharmaceutical³⁷. Recently, three US economic evaluations of pegfilgrastim have been published^38–40.

A cost-utility analysis in adult cancer patients receiving chemotherapy compared three treatment alternatives: primary prophylaxis with pegfilgrastim, primary prophylaxis with the filgrastim biopharmaceutical, and no prophylaxis³⁸. A decision-analytic model from the societal perspective was populated with data on 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. The findings showed that pegfilgrastim dominated both the filgrastim biopharmaceutical and no prophylaxis: 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 the filgrastim biopharmaceutical dropped by 26%.

A second economic evaluation calculated the incremental cost-effectiveness and cost-utility ratios of primary prophylaxis with pegfilgrastim as compared with filgrastim used for 6 days in patients with aggressive non-Hodgkin's lymphoma receiving myelosuppressive chemotherapy³⁹. A decision-analytic model was developed from a health insurer's perspective with a life-time horizon. Data for the model originated from the literature. Taking into account the benefit of optimising chemotherapy, primary prophylaxis with pegfilgrastim had a ratio of $1,494 per life-year gained or $1,677 per quality-adjusted life-year gained as 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 constructed a decision-analytic model from a health insurer's perspective to compare 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 higher⁴⁰. The model adopted a lifetime horizon and model inputs were derived from the literature. Primary prophylaxis with pegfilgrastim was found to have a ratio of $110,000 per life-year gained or $116,000 per quality-adjusted life-year gained as compared with secondary prophylaxis. The authors stated that the cost effectiveness of primary prophylaxis with pegfilgrastim was less favourable 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 the filgrastim biopharmaceutical and biosimilars. However, the authors argued that the filgrastim biopharmaceutical should have similar or worse cost effectiveness than pegfilgrastim primary prophylaxis because of its comparable or more expensive cost and comparable or worse efficacy in reducing febrile neutropenia rates. They recommended that the costs and effects of filgrastim biosimilars be compared with those of pegfilgrastim.

This section illustrated the health economic challenges involved in gaining market access for the filgrastim biopharmaceutical, the filgrastim biosimilars and the pegfilgrastim biopharmaceutical by showing 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 as compared to the filgrastim biopharmaceutical (although its cost effectiveness as compared to the filgrastim biosimilars still needs to be determined).

Conclusions

This paper has identified a number of health economic challenges involved in the process of gaining market access for biopharmaceuticals and biosimilars. There is a need for an evidence-based approach that integrates health economic considerations into the development programmes of biopharmaceuticals and biosimilars. Such an approach should be targeted at demonstrating the relative effectiveness and cost effectiveness of biopharmaceuticals and biosimilars with a view to informing registration, pricing and reimbursement decisions.

Figure 1. Outline of biotechnology products.

Table 1. Examples of biopharmaceuticals and biosimilars in Europe.

Biotechnology group	Biopharmaceutical products	Biosimilar products
Blood coagulation modulators	Factor VII, VIII, IX, X
Enzymes	Imiglucerase, alglucerase
Erythropoietins	Epoetin alpha, erythropoietin beta	Epoetin alpha, epoetin zeta
Gonadotrophins	Follitropin beta
Granulocyte colony-stimulating factors	Filgrastim, pegfilgrastim	Filgrastim
Human growth hormones	Somatropin	Somatropin
Human insulins	Insulin aspart
Interferons	Interferon alpha, beta, gamma
Interleukin-based products	Aldesleukin
Monoclonal antibodies	Abciximab, adalimumab, alemtuzumab, basiliximab, daclizumab, gemtuzumab, infliximab, palivizumab, rituximab, trastuzumab
Tissue plasminogen activators	Alteplase, reteplase, tenecteplase
Vaccines	Cholera vaccine, diphtheria tetanus and pertussis vaccine, hepatitis B surface antigen

Acknowledgements

Declaration of interest: No sources of funding were used to assist in the preparation of this manuscript. The author has no conflicts of interest that are directly relevant to the content of this manuscript.