Elsevier

Blood Reviews

Volume 28, Issue 6, November 2014, Pages 263-268
Blood Reviews

Review
Biosimilars: A cure to the U.S. health care cost conundrum?

https://doi.org/10.1016/j.blre.2014.08.003Get rights and content

Abstract

As the cost of healthcare continues to rise and patents on biologics near expiration, biosimilars are gaining visibility as a mechanism for cost reduction. Yet, the introduction of biosimilars into the U.S. market will be complex, due to the related complexity of production, research requirements, and regulatory uncertainty. The purpose of this paper is to frame the relevant issues in order to provide context for stakeholders. It is particularly crucial that clinicians understand the scientific, regulatory, legislative and economic considerations involved in order to ensure that the path to approval is consistent with their needs and that appropriate utilization occurs, once approved.

Introduction

Healthcare costs are unsustainable and stakeholders are in search of ways to bend the cost curve. One change on the horizon with the potential to temper the rise in health care costs is in the introduction of biosimilars to the U.S. market. Biologic agents are unique from traditional therapies in that they are derived from living sources and often used to treat complex conditions such as cancer and rheumatoid diseases. A biosimilar, or follow-on biologic, is an agent in which the active ingredients closely resemble that of a previously approved biologic agent. There are numerous definitions of biosimilars throughout the world, a selection of which is shown in Table 1.

Despite having been approved for a number of years in Europe, a recent survey of 470 physicians in France, Germany, Spain, Italy and the United Kingdom demonstrated that almost a quarter of physicians either hadn't heard of biosimilars or couldn't define them [1]. Some stakeholders believe that biosimilars are the same as generic small molecules, which were introduced following the passage of the Hatch Waxman Act in 1984, while others understand that the complexities of their production make the introduction of biosimilars very different. Regardless, there remains a great deal of uncertainty as to the steps and requirements involved in their approval. Differences in aspects of their production, including the manufacturing process, source of the agent, and method of extraction mean that they cannot perfectly replicate the reference agent. It is estimated that it presently takes three to five years and between $1 and $5 million to bring a traditional generic drug to market while it is anticipated to take eight to ten years and $100 to $200 million to do the same for biosimilars [2]. This difference is driven by the complexity of production, research needs, and regulatory requirements.

Both are dwarfed by the cost of initial development. A systematic review published in 2011 on the cost of drug development reported a range of cash outlays for new therapies of $92 million for drugs developed in the 1960s and 1970s to $738 million in the 1990s and 2000s [3]. The capitalized costs range from $161 million to $1.45 billion. The cost of development for more recent agents has undoubtedly increased still further.

The potential impact and role of biosimilars in clinical practice in the U.S. are substantial. While they will not be as heavily discounted as generic agents, the involved savings are still potentially dramatic. In this manuscript, we outline the critical aspects of their assessment and introduction in order to help stakeholders make informed decisions about their use moving forward. In particular, we will discuss the economic considerations, evidentiary concerns, regulatory environment at the national and state levels, and international experience, and conclude by discussing the U.S. market.

Section snippets

Economic considerations

The fact that the growth in health care spending in the U.S. is unsustainable is not a new reality. At present, health care spending constitutes 18% of the overall gross domestic product [4]. While the rate of growth has slowed more than anticipated, the drivers of this change are not fully understood and are unlikely to be sustained. Of the $2.8 trillion spent on healthcare in 2012, 10% was spent on pharmaceutical agents (~$261 billion) [4]. Biologics in particular are expected to grow to a

Regulatory environment

The regulatory considerations related to biosimilar uptake remain ill-defined and lead to some of the uncertainty as to their impact. While the primary focus to date has been on the FDA, there are state regulatory and other considerations of importance as well. As part of the Affordable Care Act in 2010 [8], the Biologics Price Competition and Innovation Act introduced the pathway for biosimilar approval. Within it, biosimilarity was defined as being “highly similar to the reference product

Evidentiary concerns

The FDA must strike the right balance between providing relative certainty of the safety of a given biosimilar and avoiding unnecessarily onerous requirements that would undermine the economic rationale for development. The requirement to demonstrate that no clinically meaningful differences exist in terms of safety, purity and potency is an appropriate bar, but remains open to interpretation. The full BLA approach at the U.S. FDA, as discussed prior and alternatively referred to as the 351(a)

International experience

While the introduction of biosimilars will be a new phenomenon in the U.S., the E.U. has over a decade of experience. As previously discussed, the initial framework was proposed nearly a decade ago by the European Medicines Agency (EMA) and has been built upon since that time, including guidance related to a variety of drug classes. A recent analysis by Grabowski et al. elucidated the uptake of the agents throughout Europe following approvals [27]. It is clear that there has been significant

U.S. market

Biosimilar discussions will become increasingly important over the next decade in the U.S. The only agent to come off patent for which there could be a biosimilar introduced to date is filgrastim. As discussed, despite filgrastim coming off patent in 2012 and approval of tbo-filgrastim by the FDA the same year, patent litigation with Amgen led to an injunction delaying tbo-filgrastim's introduction until late 2013. The agent was submitted to the FDA by Teva Pharmaceuticals as a new agent as

Practice points

  • Biosimilars are on the horizon in the U.S., although the specific requirements related to their approval are not yet fully defined.

  • Legislative battles are being waged at present around issues such as the ease or substitution and the naming of the agents that will define their ease of use. Clinicians need to be active participants in the debates.

  • While there are concerns about safety events related to biosimilars, and issues such as immunogenicity have been seen with biologics in the past, no

Challenges and proposed/potential solutions

  • Evidence development — Initially, robust clinical trials will be needed in order to ensure comfort among stakeholders, most notably clinicians, as to the comparability of biosimilars. In order to expedite agent approval and to decrease the costs of development over time, an increased reliance on analytic processes and pharmacovigilance will be critical, especially as capabilities in both fields continue to advance quickly.

  • Education — Stakeholders are not adequately educated about the risks and

Conflict of interest

Dr Lyman is PI on a research grant on risk factors for febrile neutropenia to the Fred Hutchinson Cancer Research Center from Amgen.

References (38)

  • Center for Drug Evalation and Research

    Guidance for industry: quality considerations in demonstrating biosimilarity to a reference protein product

  • Center for Drug Evalation and Research

    Guidance for industry: scientific considerations in demonstrating biosimilarity to a reference protein product

  • Center for Drug Evalation and Research

    Guidance for industry: formal meetings between FDA and biosimilar biological product sponsors or applicants

  • S. Kozlowski et al.

    Developing the nation's biosimilars program

    N Engl J Med

    (2011)
  • European Medicines Agency

    Guidance on similar biological medicinal products

  • European Medicines Agency

    Guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant erythropoietins (revision)

  • European Medicines Agency

    Guidance on similar medicinal products containing recombinant erythropoietins

  • European Medicines Agency

    European public assessment reports for filgrastim

  • European Medicines Agency

    Guideline on similar biological medicinal products containing recombinant granulocyte-stimulating factor

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