The three-arm clinical trial design aims to compare U.S.- and EU-sourced reference products to the biosimilar in one trial, while generating the requisite pharmacokinetic(PK)/pharmacodynamic (PD) data to support approval in the United States and Europe. Pfizer started its fifth three-arm Phase I trial for its biosimilar bevacizumab molecule (PF-06439535) in February 2014, firmly embedding this as a strategy for its biosimilar development program. Pfizer is not alone, however; between December 2011 and April 16th 2014, fourteen biosimilar molecules have entered three-arm Phase I trials.
At the 18th European Generic Medicines Association (EGA) Annual Conference in June 2012, the European Commission (EC) announced that it will permit the use of reference product batches from other ICH territories (i.e., the United States or Japan) outside the European Economic Area (EEA) to aid the global development of biosimilars and reduce the need for manufacturers to repeat clinical trials unnecessarily. This change in EMA guidance will come into effect when the EMA's overarching biosimilars guidelines are finalized, possibly later in 2014. Under current EMA guidelines for biosimilar development, data comparing a biosimilar to a non-EEA-sourced reference product may only be used as supportive evidence in a regulatory dossier. Biosimilar manufacturers will have to demonstrate that the non-EEA reference product is representative of the EMA-approved reference product by submitting bridging data in the form of structural and functional comparisons, or clinical PK/PD tests. The nature of the required bridging data will be decided at the discretion of the EMA. Even though we are still waiting for the EMA to finalize its overarching biosimilars guidelines, companies are already modifying their clinical development strategies to take advantage of this change. Boehringer Ingelheim took the lead, with three three-arm trials underway, but other companies such as Amgen, Pfizer, Samsung Bioepis (a joint venture between Samsung Biologics and Biogen Idec) have followed suit.
One of the benefits of conducting three-arm Phase I trials to ascertain biosimilarity to EEA- and U.S.-sourced reference products is that it gives manufacturers the opportunity to identify any differences between the EEA- and U.S.-sourced reference products early in the clinical development process. If clinical differences are identified between the two sources of reference product, this gives manufacturers the opportunity to adapt their strategy accordingly. If three-armed Phase I trials are not undertaken and manufacturers discover differences between the reference products in a later bridging study, costly duplication of Phase III trials could be required to gain access to the United States and European markets. Biosimilar sponsors can also streamline Phase III development by conducting only one efficacy trial with one (EU or U.S.) reference product, if the biosimilar was comparable to both in the three-arm Phase I trial. Early entrants to the biosimilars sector, such as Celltrion, who only used the EU reference product during its clinical trials for Remsima (biosimilar infliximab), conducted a separate bridging study to support FDA approval; after receiving approval for Remsima in Europe, in August 2013, Celltrion was required to conduct a separate bridging study comparing Remsima with EU and U.S.-sourced reference products. The bridging study which started in October 2013 lasted six months. Celltrion is pursuing FDA approval this year, which it expects to be granted in early 2015, if patent litigation allows.
The benefits of the three-arm Phase I trial strategy will only be felt if the design is acceptable to the FDA, as well as the EMA. The FDA draft guidelines for biosimilars state that biosimilar candidates may be compared to non-FDA-approved reference products but bridging data to the FDA approved product will be required, similar to the EMA draft revised guidance. Manufacturers will have to discuss specific details of any bridging studies with the FDA.
The three-arm Phase I trial strategy is unlikely to accelerate the development process of biosimilars in Japan, however. In most instances, for a biosimilar developed using a European or U.S.-sourced reference product and conducted in those regions, a Phase I bridging study in Japanese patients will be required for a biosimilar, not only to provide a bridge to the Japanese-sourced reference product, but also to show that there are no differences between the biosimilar and reference product in terms of safety and efficacy due to ethnicity.
With the EGA estimating biosimilar development to cost between $100 to $150 million, it is imperative for biosimilar manufacturers to minimize development costs wherever possible. A Phase I three-arm trial is one avenue by which to do so, and can accelerate the approval process in the EU and United States.
Adelina Adjei is a data analyst for biosimilars research at Decision Resources Group.
For more information on the research behind these findings, go to Decision Resources Group's product page on Biosimilars Advisory Service: Corporate Strategies.