Complete response letters (CRLs) were issued by the FDA recently for two biosimilar versions of Roche’s Rituxan—first to Celltrion and Teva on April 9 for Truxima and then to the Sandoz division of Novartis on May 3 for Rixathon, over two months ahead of its Prescription Drug User Fee Act (PDUFA) date, effectively stalling rituximab biosimilar development in the US.

Furthermore, both Pfizer and Celltrion received CRLs from the FDA for their biosimilar versions of Herceptin. In addition to delaying competition in the US for Roche’s blockbuster drug, Rituxan (another Herceptin biosimilar, Ogivri, is already FDA-approved), the rejections, along with protracted legal battles over patents, could ultimately serve to contribute to increased costs for biosimilar development. Depending on the type of issue that triggered the rejection, the delays in terms of either cost or time can be significant.

Poor aseptic practices at Celltrion’s manufacturing plant in South Korea contributed to the reason for the rejection of Truxima’s biologics license application (BLA) in May, as well as that of its Herceptin biosimilar. As a result, launch delays of up to two quarters or more are likely. However, Pfizer disclosed that the FDA was seeking additional technical information for its Herceptin biosimilar, but that safety or clinical data were not involved in the decision. Sandoz has not yet disclosed the reason for triggering the CRL for Rixathon, and has stated its commitment to holding further discussions with the FDA.

Challenges in biosimilar development

Manufacturing issues are often complicated in nature, being both costly and time-consuming to correct. In addition, given that biosimilar developers are concentrated in emerging markets, those attempting to gain entry to the US are facing a higher bar to hurdle in terms of development standards and manufacturing practices.

Approval strategies for biosimilars in the US may differ from that in other countries, and do not necessarily include all indications covered by the originator drug. Rixathon was approved in Europe in June 2017 for both the oncology and autoimmune approved indications of Rituxan/MabThera but Sandoz’s application to the FDA included only the oncology indications.

Furthermore, in cases where patent exclusivity for certain indications is in force, marketing of biosimilars in all approved indications may be delayed, limiting the ability of the company to recoup development costs in a timely manner. An example of this is Biocon and Mylan’s Herceptin biosimilar, Ogivri, which is approved for both HER-2-positive breast cancer and metastatic gastric or gastroesophageal cancers, but cannot yet be marketed for gastric cancer due to Roche’s exclusive license for Herceptin in this indication.

By not requiring the same comprehensive panel of non-clinical and clinical data as that for innovator drugs, the accelerated pathway was intended to facilitate and reduce the costs of biosimilar drug development. However, both previous uncertainties about the approval pathway in the US as well as a great deal of patent litigation have translated into a slow start for biosimilars gaining traction in the US; now the recent numbers of CRLs received by developers are not only adding to the delay but potentially also to the cost.

Further complicating the mix of issues to consider when embarking on biosimilar development, discounts given for biosimilars over originator drug not only vary between markets, but the actual price may not reflect the listed discount once the biosimilar launches. While the reasons for the delays in development vary from more straightforward to address to those that are more complex, the increased numbers of recent delays in the US are likely to prompt a closer examination by stakeholders of the cost-benefit ratio of pursuing biosimilar development.

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