An International Approach to Boosting the US Biosimilars Market


Chip Davis of the Association for Accessible Medicines argues that learning from the European biosimilars approval experience could speed up patient access to these complex drugs in the USA.


Advancements in biologic research and development have brought forth life-saving treatments for patients with cancer as well as such chronic illnesses such as multiple sclerosis, diabetes, rheumatoid arthritis and Crohn’s disease. Biosimilars, which are highly similar to their reference biologics, promise to make these treatments more accessible by providing competition in the market.

The potential for biosimilars is vast, with the RAND Corporation estimating USD 54 billion in savings over 10 years, and patient access to biologic medicine broadly is expected to increase significantly as a result of biosimilar availability. These are savings that would be passed onto patients, taxpayers and the healthcare system as a whole.

Biosimilars have made a great deal more headway in Europe, where they have been in use for more than a decade than in the US, where the first biosimilar was approved in 2015. The European Medicines Agency (EMA) has approved more than 50 biosimilar drugs. In the United States, by contrast, the Food and Drug Administration (FDA) has approved just 20 biosimilars. We should explore leveraging the global experience with biosimilars, including that in Europe, in order to expedite US approvals for these complex drugs.

A “Global Comparator” program is one promising mechanism for achieving greater biosimilar accessibility. The FDA could allow the use of non-US reference product in the development of US biosimilars without the need for expensive clinical bridging studies


The Proposal

The FDA would allow the use of non-US reference products if certain requirements are met—for example, approval by a regulatory authority that has formally adopted and implemented International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use  (ICH) guidelines. The FDA could approve a biosimilar based upon clinical studies using a non-US licensed comparator product (“foreign comparator” or “global reference comparator”), without the need to conduct bridging studies with the US-licensed Reference Product (RP) when other circumstances, data, and information are sufficient to establish the necessary bridge. This shift would significantly reduce the development costs of biosimilars and interchangeable biological products by obviating the need for unnecessary testing. FDA and other global regulatory authorities like the EMA and World Health Organization (WHO) have been moving this direction in recent years.


The Foundation

The Biologics Price Competition and Innovation Act (BPCIA) created a regulatory framework in the US for a strong foundation for an expansive and far-reaching biosimilars market. We have already established a framework where biosimilars are clinically equivalent to, or just as safe and effective as, their reference medicines. There is a growing global chorus of stakeholders acknowledging this conclusion, especially as the market for them matures and stakeholders analyze the significant breadth of data related to their safety and effectiveness.

In July 2018, the FDA released its Biosimilars Action Plan, which outlined key actions the Agency will take to encourage innovation and competition. As part of this plan, the FDA is “exploring the potential for entering into new data sharing agreements with foreign regulators to facilitate the increased use of non-US-licensed comparator products in certain studies to support a biosimilar application.” In particular, the FDA is strengthening partnerships with regulatory authorities in Europe, Japan and Canada. The FDA also intends to update guidance related to biosimilars and to hold public meetings and hearings to seek public input on proposed actions. While the FDA has not proposed a specific guidance document to address the biosimilar bridging study issue, it notes that it will undertake efforts “to harmonize international regulation of biosimilars and the acceptance of non-US comparator products” and has continued to move in this direction with recent guidance.


The Precedent

The FDA has already exercised this discretion by allowing 351(k) applicants to use foreign comparators in certain circumstances.  Certain administrative actions would be helpful to implement the shift, such as entering into new or revised data sharing cooperative agreements with foreign regulatory authorities. Furthermore, this change would align processes in the US with the concept of a “foreign-source reference biotherapeutic product” as is being proposed by the World Health Organization.


The Science

 The scientific rationale for this approach is neatly summed up by Christopher J. Webster (BioApprovals) and Gillian R. Woollett (Avalere) in their 2017 article, “A ‘Global Reference’ Comparator for Biosimilar Development”:

Because regulators in the different jurisdictions have similar technical experience and are applying the same principles of comparability (via shared [ICH] guidelines), and because the changed products in each of their jurisdictions have a common origin and share the same core data describing their structure and functions, the material representativity of the [foreign comparator for the RP] is preserved – any quality differences between the two product versions can be considered inconsequential as regards their use as comparators for biosimilar development.


The Economics

The process of developing a biosimilar is far lengthier and more expensive than small-molecule generic development. Biosimilars can take eight or more years to develop at a cost between USD 100 million and 300 million, compared to three years and between USD 1 million and 5 million for a small molecule generic. To be sure, the barriers to development for these products are high, enough so that some commentators have proposed giving up on biosimilars and instead instituting price controls on biologics.

Our member companies estimate that at least 50-100 subjects would be required for each comparative PK or PD clinical bridging study for a single biosimilar product in a single jurisdiction, with an attendant cost of USD 5-10 million in development costs. Given that approximately 60 biosimilars are currently in the FDA Biosimilar Development Program, the industry-wide costs for clinical bridging studies are estimated to be between USD 300 and 600 million.

Despite these high costs, clinical bridging studies add little value to scientific and regulatory decision-making regarding biosimilarity.  Thus, bridging between foreign comparators and the US-licensed RP exposes subjects to unnecessary clinical testing.  During Congressional hearings on biosimilar legislation, Dr Janet Woodcock, Director of the FDA’s Center for Drug Evaluation and Research, testified that “[w]here trials aren’t needed, it is … of questionable ethics to repeat them. So the use of human subjects for trials that are not needed or done simply to check a box on a regulatory requirement are not desirable.”

Dr Woodcock is right to concentrate FDA resources where they are most needed, rather than reviewing studies that repeat rigorous work done elsewhere. By leveraging Europe’s experience with biosimilars, the US can accelerate progress on biosimilar accessibility and lower costs for patients and the overall healthcare system.

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