On April 28, 2015, the U.S. Food and Drug Administration (FDA) released the much-anticipated final guidance documents related to implementation of the Biologics Price Control and Innovation Act of 2009 (BPCIA). Not surprisingly, the FDA’s three final guidance documents are substantially similar to the draft guidance issued in February 2012, discussed here, and reflect the FDA’s recent statements and actions leading to the approval of Sandoz’s Zarxio® product (filgrastim-sndz). The three final guidance documents can be found here:

  1. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (“SC”) (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf);
  2. Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product (“QC”) (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291134.pdf); and
  3. Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (“Q & A”) (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM444661.pdf).

The final guidance documents address broad concepts associated with demonstrating biosimilarity, including an emphasis on structural and functional characterization (SC at 9-11), human pharmacokinetic (PK) and pharmacodynamic (PD) data (SC at 13-17), comparative human clinical studies if there is “residual uncertainty” regarding clinically meaningful differences (SC at 18-20), non-U.S. licensed reference product comparators (SC at 6), extrapolation across indications (SC at 21-22); expression systems and manufacturing processes (QC at 10-11), analysis of the reference product (QC at 14-15), and analysis of the finished drug product (QC at 15-16). The final guidance documents do not, however, address interchangeability, as the FDA indicated that “[g]eneral scientific issues relating to the demonstration of interchangeability will be addressed separately.” (SC at 3, n.6.) 

Like the draft guidance, the final guidance recommends that biosimilar applicants utilize a “stepwise approach to developing data and information needed to support a demonstration of biosimilarity.” (SC at 7.) According to the FDA, this stepwise approach will help the applicant and the agency evaluate “the extent to which . . . residual uncertainty” remains concerning the biosimilarity of the proposed product to the reference product. (Id.) As part of this stepwise approach, the FDA “encourages sponsors to consult extensively with the Agency . . . throughout development as needed.” (SC at 8.) Indeed, the FDA indicated that early discussion with the FDA “will facilitate biosimilar development.” (SC at 23.) 

The FDA also reiterated its commitment to considering the “totality-of-the-evidence” when evaluating the data and information contained in a biosimilar application and will apply a “risk-based approach.” (SC at 8.) Applying the totality-of-the-evidence approach, the FDA indicated that an applicant could still demonstrate biosimilarity even if there are formulation or minor structural differences, so long those differences do not result in a “clinically meaningful” difference between the biosimilar and reference product. (Id.) The FDA’s implementation of the totality-of-the-evidence approach can be seen in the Agency’s recent review and approval of Zarxio®, where the review committee relied on Zarxio’s extensive use in Europe and the fact that Sandoz was able to establish biosimilarity despite using a different buffering system. 

Although human comparative clinical studies will likely be needed, at least in the immediate future, the FDA did indicate that such studies might only be needed “to support a demonstration of biosimilarity if there is residual uncertainty about whether there are clinically meaningful differences between the proposed product and the reference product” after conducting structural and functional characterizations, animal testing, human PK and PD studies and clinical immunogenicity assessment. (SC at 18.) “A sponsor should provide a scientific justification if it believes that a comparative clinical study is not necessary.” (Id.) 

Biosimilar development is being conducted on a global scale with several products already on the market in different countries. In view of this reality and the BPCIA’s requirement that a proposed product must be biosimilar to a single reference product previously licensed by the FDA, potential biosimilar applicants want to know whether the FDA would allow comparison of animal and human clinical data to a non-U.S.-licensed product. According to the FDA, the short answer is “Yes.” (Q&A at 8; SC at 7.) The FDA made clear however, that “as a scientific matter,” an application must contain at least one PK study and, if appropriate, at least one PD study comparing the biosimilar product to the U.S.-licensed product. (Q&A at 8.) If comparisons to a non-U.S.-licensed product are made, the applicant “should provide adequate data or information to scientifically justify the relevance of these comparative data to an assessment of biosimilarity and establish an acceptable bridge to the U.S.-licensed reference product.” (Q&A at 8; SC at 6.) 

As we now know from the recent approval of Zarxio®, the FDA will allow extrapolations to other indications if the proposed product meets the requirements for licensure as a biosimilar. In order to extrapolate, applicants “need to provide sufficient scientific justification” for such an extrapolation, and should address the mechanism of action(s) in each additional indication, PK, bio-distribution, immunogenicity, and expected toxicities of the biosimilar product in different patient populations. (SC at 21.) 

Finally, the FDA provided contact information if an applicant has a question about its proposed biosimilar development program. If the reference product is regulated by the Center for Drug Evaluation and Research (CDER), applicants are instructed to contact the Therapeutic Biologics and Biosimilars Team at 301-796-0700. If the reference product is regulated by the Center for Biologics Evaluation and Research (CBER), applicants should contact the Office of Communication, Outreach, and Development at 800-835-4709 or 240-402-7800, or email ocod@fda.hhs.gov. Finally, with general questions concerning the FDA’s implementation of the BPCIA, applicants and reference product sponsors should contact Sandra Benton in CDER’s Office of Medical Policy at 301-796-2500. 

With the recent approval of Zarxio®, and several additional biosimilar applications in the queue from Celltrion/Hospira (biosimilar to Remicade®), Apotex (biosimilar to Neupogen®), and Hospira (biosimilar to Epogen® and Procrit®), the FDA should provide, over the coming months, further insights on the requirements necessary to obtain approval of much more complex biosimilar products.