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This scenario seeks to limit animal and clinical studies to only those needed to eliminate residual uncertainty about product performance. Although innovators maintain that clinical trials still are needed to fully examine immunogenicity and other unique attributes of proteins and monoclonal antibodies, biosimilar developers look to extensive product characterization and to pharmacokinetic (PK) or pharmacodynamic (PD) studies to address these concerns.
A key issue in developing and gaining Food and Drug Administration approval of a new biosimilar is the extent of pre-clinical and clinical studies needed to document product “similarity,” as opposed to safety and efficacy. Now with one approved biosimilar under its belt, and dozens more under review and in development, FDA’s biosimilar development program is moving “beyond the finish line,” says Steven Kozlowski, director the Office of Biotechnology Products (OBP) in the Center for Drug Evaluation and Research (CDER). But agency officials still have much to do to address critical issues related to product analysis and testing, as discussed by regulatory officials and sponsors at the October “Biosimilars 2015” conference sponsored by the Drug Information Association (DIA).
As of September 2015, FDA had received six biosimilar applications to reference products, the latest filed in early October, and has approved one – Sandoz’ Zarxio (filgrastim-sndz). Of equal importance, some 57 biosimilars for 16 reference products have enrolled in FDA’s Biosimilar Product Development program, and sponsors are seeking preliminary advice on another 27 projects.
Biosimilar development in the U.S. emphasizes the use of analytical tools to demonstrate product quality and an absence of clinically meaningful differences between the new therapy and its reference drug. FDA backs a “step-wise” approach to determining “how close is close enough” for the two products, with risk assessment applied to help identify those attributes that are most important for ensuring product quality and similarity, and those that matter less.
This scenario seeks to limit animal and clinical studies to only those needed to eliminate residual uncertainty about product performance. Although innovators maintain that clinical trials still are needed to fully examine immunogenicity and other unique attributes of proteins and monoclonal antibodies, biosimilar developers look to extensive product characterization and to pharmacokinetic (PK) or pharmacodynamic (PD) studies to address these concerns. A related issue is to what extent biosimilar developers should be allowed to extrapolate evidence to additional indications to the reference product. Reducing the number of clinical trials through extensive product characterization and data extrapolation can help avoid exposing more individuals than necessary to the risks of clinical trials, and biosimilar manufacturers expect that continued improvements in technology will further reduce the need to study these products in patients.
But at this point in its program, FDA officials assume that some clinical testing is necessary to confirm biosimilarity and product safety, and FDA review teams are available to provide advice to sponsors on appropriate study designs of adequate size and duration. Unlike innovator testing, biosimilar development should not involve large pivotal studies with objective response rates, but rely on smaller comparative trials and immunogenicity studies. But when non-U.S.-licensed reference products are involved, bridging study data will be requested. Immunogenicity studies should be designed to assess titers, persistence, impact on PK, and clinical sequelae, explained Steven Lemery, lead medical officer in the Office of Hematology and Oncology Products in CDER’s Office of New Drugs (OND). And sponsors should consider the mechanism of action for each condition of use and whether different patient populations experience differences in PK, immunogenicity and expected toxicities.
Further FDA guidance on appropriate statistical analysis of production data and results from pharmacologic and clinical studies should help address these and other research design issues. Kozlowski explained that rigorous statistical analyses should be part of the evidence submitted by a sponsor to document biosimilarity, but that such calculations won’t support yes-no approval decisions by themselves.
In the future, this “totality of evidence” approach to biosimilar development will be key to documenting product interchangeability, and additional FDA guidance is expected to further define the scope of clinical data required for such products. Sponsors and FDA already are exploring the nature of cross-over studies for target populations, appropriate study endpoints, number of switches and duration of studies to support interchangeability, explained Hillel Cohen, executive director for scientific affairs at Sandoz. He noted that some immunogenicity issues are hard to evaluate in switching studies, and that postmarket pharmacovigilance may assume added importance for evaluating biosimilars over the long term.
As sponsors look to utilize data generated in one region to support biosimilar development in other markets, FDA officials are engaging with regulatory colleagues to establish common standards and regulatory proposals to facilitate global programs. Main issues for FDA are whether sponsors may submit data produced in other markets or use a non-U.S.-licensed comparator in studies to support U.S. licensure, reported OND associate director for therapeutic biologics Leah Christl at the DIA conference. The European Union has authorized nearly 20 biosimilars since 2006, providing a model for how biosimilars can meet regulatory standards and play an important role in expanding patient access to needed medicines. But FDA policies and requirements for biosimilars must fit its legal structure and regulations.
These and other issues are being examined by a Biosimilars Cluster, which meets several times a year to seek “scientific alignment” of policies and development issues for biosimilar oversight by FDA, the European Medicines Agency (EMA), Health Canada and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA). Similarly the Biosimilars Working Group of the International Pharmaceutical Regulators Forum (IPRF) periodically discusses issues and challenges in regulating biosimilars in these countries as well as South America, Asia and other regions. Biosimilar sponsors may seek “parallel scientific advice” from FDA and EMA, Christl adds, noting that full program “harmonization” will be difficult to achieve.
The adequacy of funding to support FDA’s resource-intensive biosimilar development program will be examined in the coming months as part of the process for reauthorizing biosimilar user fees in 2017. FDA is holding an initial public meeting in December to launch negotiations on the fee structure and other aspects of the program. To continue FDA’s extensive assistance to sponsors on shaping R&D programs, FDA may be looking for manufacturers to pay upfront an even larger portion of the biosimilar application fee, a unique feature of this program.