By Dr. Bob Roth
Several years ago, after the first follow-on growth hormone replacement therapeutics Omnitrope® and Valtropin® were approved by the FDA under the standard drug approval pathway, we proposed that development programs for these types of products would remain very extensive despite their promise for development and cost savings. Such products, though approved as drugs, were given the moniker “biosimilars” because they demonstrated the ability to be interchangeable with an already licensed biological product.
While biosimilar products have been commercially available in Europe for nearly a decade, the U.S. FDA did not approve a biosimilar product until 2015. Before this, the regulatory pathway for obtaining a biosimilar approval in the U.S. wasn’t even defined. However, the 2010 amendment to the Public Health Services Act established that long-sought route and in March of 2015, the FDA announced the approval of the first U.S. biosimilar, branded as Zarxio™.
Zarxio™ (biosimilar version of Neupogen®, recombinant filgrastim/GCSF for febrile neutropenia and related indications) became the first FDA-approved BLA biosimilar and it paved the way for countless other products. There now exists a regulatory route for approval of follow-on protein therapeutics via both drug and biologic pathways (505(b)(2) and 351(k), respectively), depending on the Center within the FDA which approved the innovator product.
The likely development requirements for a biosimilar BLA product seemed quite significant when the FDA published a general scientific considerations guidance and accompanying quality and pharmacology guidances. However, the FDA acknowledged that data requirements would be product-specific to a certain extent, and that certain information could be deemed necessary and other data unnecessary for a particular biosimilar program with FDA’s agreement. With the approval of Zarxio it became possible to get an initial view of the FDA’s approach to approvability of biosimilar BLA products via the 351(k) pathway.
Comparing the U.S. and EU Approval Processes
The approval of Zarxio also made it possible to contrast the approaches taken by the U.S. FDA and the EU for this product.Based on EPARS review of the EU submission file for Zarxio approved in 2009 (named Zarzio for the EU) and data summarized in the FDA Advisory Committee briefing package for eventual FDA approval in 2015, we can start to evaluate what a successful biosimilar BLA data package looks like.
Components of a Successful Biosimilar BLA Data Package
- Very extensive comparative chemical characterization to Neupogen showing similarity.
- In vitro binding experiments showing equivalent affinity of the two drugs for their receptors, and several animal studies to evaluate toxicity, toxicokinetics, pharmacodynamics and local tolerance.
- Several human comparative pharmacokinetic/pharmacodynamic studies in healthy volunteers.
- For the EU approval, no patient efficacy studies were performed; efficacy was concluded on the basis of comparative pharmacodynamic endpoints in healthy volunteers.
- For the US approval, a head-to-head non-inferiority trial vs. Neupogen in cancer patients provided pivotal evidence of efficacy, supplementing comparative pharmacodynamic endpoints in healthy volunteers.
- For EU approval, a long-term non-comparative safety study in cancer patients was conducted.
- For the US approval, comparative safety vs. Neupogen in the phase 3 cancer trial supplemented the non-comparative safety study in cancer patients.
Of particular interest to us, efficacy for the EU approval was concluded solely on the basis of comparative in vitro binding experiments and pharmacodynamic endpoints in healthy human volunteers, whereas the U.S. data package included a pivotal clinical non-inferiority study demonstrating therapeutic equivalence to Neupogen. Immunogenicity risk for Zarxio vs. Neupogen was also shown directly in the U.S. development program but could only be compared to Neupogen using historical control data.
In addition, we also note with interest that the development of the biosimilar product for the U.S. approval included test drug switching data in the pivotal phase 3 trial, a recommendation from FDA’s draft guidance focused on biosimilar quality issues but not in the more general scientific considerations guidance.
U.S. and EU Biosimilar Cost-Benefit Considerations
Although we are not privy to the costs for the clinical development portion of the U.S. data package, it is commonly cited that for long and complex clinical trials the costs for late-stage clinical work can be in the range $16,000-$25,000 per subject or even higher. Development time is also greatly expanded when long-term clinical trials are conducted, especially if many sites and investigators are needed and if there is a focus on chronic dose safety including specialized tests such as immunogenicity.
The EU discount for the biosimilar was initially set at approximately 15% as in the U.S. but later raised to 20-30% as noted in this press release. This suggests that the less onerous EU development program may have translated into lower costs to patients and therefore a more favorable cost-benefit for both patients and the pharma company.
Assuming that there is some reasonable relationship between development cost and sponsor reimbursement, is the additional cost to U.S. patients because of more clinical development cost worth it to ensure the acceptability of the product as a biosimilar? How justified are the extensive development programs and patient costs when the stated intent of an abbreviated licensure pathway is to make treatments more affordable?
Since the generic drug paradigm based solely on comparative characteristics and bioequivalence is unlikely to ever prove sufficient for most complex biological drug products, one is left to wonder just how cost-effective is the biosimilar approval pathway and associated data requirements.
Get Help with the FDA Approval Process
Are you in the process of developing a biosimilar or other FDA-regulated product? We can help you get through the FDA successfully.
The Weinberg Group has over 35 years of experience providing biotech, medical device, and pharmaceutical consulting services to companies of every size across the world. Our experienced team of FDA consultants specializes in providing efficient drug development pathways and compliance solutions.
Robert Roth, M.D., Ph.D., is Vice President and Worldwide Medical Director at The Weinberg Group, the world’s leading food and drug consulting firm. If you have any questions or thoughts on this blog post or others, please contact us.
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