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Manufacturing and in-depth characterization provide basis for demonstrating product equivalence.
FDA officials are mapping out procedures and policies for establishing an abbreviated pathway for testing and developing safe and effective biosimilar products. Because the regulatory framework for conventional generic drugs does not fit these more complex products, FDA is adopting a "weight of evidence" approach for evaluating biosimilars, starting with extensive comparative analysis and functional studies to determine what preclinical and clinical studies may be required. The "residual uncertainty" that remains from physical analysis is key to determining the size and scope of further testing, explained Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), at a September conference on biosimilars sponsored by FDA and the Drug Information Association (DIA). Woodcock noted that this heavy reliance on physical comparison represents "a paradigm shift" in how FDA documents drug safety and efficacy.
FDA laid out its basic approach for biosimilar development in three draft guidance documents published in February 2012, and a CDER/Center for Biologics Evaluation and Research (CBER) Biosimilar Implementation Committee is weighing comments and further changes. Drug-review staff members are talking to manufacturers about biosimilar development options, as seen in 47 requests for pre-investigational new drug (IND) meetings on proposed biosimilars to 11 reference products, as of early October. Agency staffers have held 30 meetings, and 12 INDs have been filed for possible biosimilars, some involving new development programs and some building on data from products already licensed in Europe. This advisory program is highly work-intensive for FDA, because each meeting with a sponsor entails at least four internal sessions and consultation with CDER and CBER biosimilar review committees to ensure that staff advice is consistent across divisions.
Amidst all the discussion, the agency still awaits its first official 351(k) biosimilar application, as authorized by the Biologics Price Competition and Innovation Act (BPCI), which was enacted through the Affordable Care Act of 2010. Teva Pharmaceuticals recently received FDA approval for its version of Amgen's Neupogen (filgrastim), but opted for a biological license application (BLA) instead of the new route. This approach gives Teva 12-years exclusivity for its product and avoids the complex patent dispute resolution process established by BPCI.
Added resources to support FDA meetings and advice will come from the Biosimilar User Fee Act (BSUFA), which was included in the July 2012 FDA Safety and Innovation Act (FDASIA). It authorizes fees for biosimilars that are similar to those for new drugs and biologics, but "frontloads" the program by allowing FDA to collect a Biosimilar Biological Product Development (BPD) fee—10% of the nearly $2 million application fee—when a sponsor holds its first official meeting with FDA or files an IND. Another 10% is paid every year that the IND remains active, but total BPD fees will be subtracted from a future BLA application fee so that the final payment remains the same as for other new drugs.
In addition to technical and scientific challenges, a number of legal and regulatory issues will determine the development path for a new biosimilar. A convoluted process for addressing exclusivity and patent rights presents a clear challenge, and there is considerable debate over biosimilar names and product codes. The size and shape of clinical studies remains uncertain, along with questions about non-US comparators and bridging studies. Interchangeability is the ultimate goal for most biosimilars manufacturers, but FDA indicates that such a designation may require more extensive test data. All sides anticipate lawsuits, citizens' petitions, and other legal battles to resolve these and other controversies.
Despite these uncertainties, the first step for manufacturers is to develop a clear analytical plan for demonstrating biosimilarity of a follow-on to a reference product. A "step-wise" approach for doing this was laid out by CDER officials at the DIA meeting and subsequently by Steve Kozlowski, director of CDER's Office of Biotechnology Products (OBP), at the Generic Pharmaceutical Association's (GPhA) fall 2012 conference. Kozlowski observed that manufacturing and product analysis are usually at the "low end of the totem pole" in drug development, but that a "totality of evidence," starting with structural and functional characterization, provides a foundation for determining the scope of preclinical and clinical studies for a biosimilar. "Once you know how close you are," Kozlowski explained, "the rest follows."
To make the most of an initial advisory meeting with FDA, sponsors should have a clear rationale for product development, with early characterization data for the proposed biosimilar and reference product lots and justification for as much of the analytical approach as possible. In-depth characterization assay development is desirable, as are preliminary analytical functional similarity studies and formulation studies. It also may help to have validated research and stability assays to support an IND.
"Know your protein" is a main FDA theme for biosimilar development. Selection of analytical test methods should be based on the nature of the protein and knowledge of its structure. Agency staff wants to know which attributes are important and how the relationship between protein attributes and the clinical safety and efficacy profile can predict "clinical similarity." Also important is whether differences between a chosen expression system and that of the reference product will significantly affect process- and product-related substances and impurities, how differences in the impurity profile or in excipients will affect safety, and the strengths and weaknesses of each analytical method.
FDA's draft guidance on quality considerations for biosimilars describes a broad range of analytical studies that may be relevant, including assessment of expression system, physicochemical properties, functional activities, receptor binding, immunochemical properties, impurities, reference product, and stability. Protein evaluation stands to benefit from a growing number of analytical tools, including mass spectrometry, peptide mapping and chromatography to assess amino acid sequence, protein folding, subunit interactions, heterogeneity, glycosylation, PEGylation, bioactivity, and other methods.
Advances in manufacturing science and adoption of quality-by-design approaches may support comparative assessment using a fingerprint-like analysis or "super characterization" approach that involves evaluating combinations of attributes using orthogonal methods. It is not clear whether biotech manufacturing processes are too variable to allow for a fingerprinting approach, Kozlowski explained at the GPhA conference, but he anticipates that upfront efforts to select appropriate cell lines will permit manufacturers to deliver an exact desired product.
Transparency also is important. It is better for a manufacturer to acknowledge uncertainties from test results and to seek advice from FDA for dealing with these issues than to ignore or hide discrepancies. FDA advises manufacturers to carefully consider the importance of differences in expression systems and the need to justify minor modifications in an amino acid sequence.
At the same time, FDA is trying to be flexible, Kozlowski emphasized, noting that differences in formulation from the reference product may be acceptable, as well as alternative delivery devices or container-closure systems. Applicants may market a proposed biosimilar for fewer than all conditions of use and presentations for which the reference product is licensed.
"The more analytical data one has up front, the more targeted the rest of development can be," according to Koslowsky. Although FDA expects that sponsors will have to conduct at least one immunogenicity study, Koslowski says that "the door is open," to the concept that "added studies may not be necessary."
Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, firstname.lastname@example.org
Read Jill's blogs at PharmTech.com/wechsler