CENTER FOR BIOLOGICS EVALUATION AND RESEARCH/CENTER FOR DRUG EVALUATION AND RESEARCH (CBER/CDER)
The legal pathway for the approval of biosimilars or "generic" versions of biologics has been addressed recently by various pieces of legislation. See, e.g., Access to Life-Saving Medicine Act (H.R. 1038/S. 623); Patent Protection and Innovative Biologics Medicines Act of 2007 (H.R. 1956); Affordable Biologics for Consumers Act (S. 1505); Biologics Price Competition and Innovation Act of 2007 (S. 1695); and, most recently, Pathway for Biosimilars Act (H.R. 5629). The area has been controversial for a variety of complex regulatory and scientific reasons (see Part III, CDER/CBER). The primary problem is that the Hatch-Waxman legislative approach for generic drugs is much more difficult to adapt to biologics, in part because of their more complex chemical structures.
Some of the scientific issues relate to the criteria, such as clinical immunogenicity and other data, that must be provided to satisfy abbreviated requirements for obtaining marketing approval of follow-on biologics, which typically are proteins. The information that is necessary to demonstrate interchangeability or substitutability of the biosimilar with the innovator product, and the market and data exclusivity protections that should be granted innovator products also are issues. The nomenclature used to name such biosimilars is problematic, too, because of the potential to substitute products with the same established name. The mechanism for resolution of patent conflicts, usually before marketing approval is granted, is another difficult area. Many believe that it is important to clear up patent challenges before approval is granted, rather than after, because of the potential market disruptions that could occur as a result of infringement and other court actions.
H.R. 5629 provides that certain studies must be submitted to license a product as a biosimilar, although FDA can waive these data requirements, except in the case of immunogenicity where other prerequisites must be met. FDA must issue a guidance on interchangeability that it is scientifically feasible for a particular product class. The first interchangeable biosimilar product is provided a period of exclusivity of 2 years. Innovator biological products are provided 12 years of data exclusivity with 2 additional years for a new indication if supplemental approval is obtained during the 8-year period following licensure and provided that the new indication would be a significant improvement compared to marketed products in the treatment, diagnosis, or prevention of disease. Two years of pediatric exclusivity is also available. Unique names must be assigned to a biosimilar that differentiates it from the relevant innovator product and from any other biosimilars that are licensed with reference to the same innovator. A complex system of resolving patent matters is also provided. No biosimilar status is afforded listed select agents and toxins, for reasons that are unclear. As might be expected, innovator and generic drug companies typically have very different views on many of these issues, particularly the exclusivity protections.
In an attempt to reach some type of stakeholder consensus, the Subcommittee on Health, House Committee on Energy and Commerce, recently sent on April 3, 2008 a letter (available at http://energycommerce.house.gov/Press_110/index_110.shtml#Letters) to a variety of organizations seeking input on the contents of follow-on biologics legislation. Different organizations, such as AARP, AFL-CIO, NORD, drug trade associations and drug companies, investors, and others were among the 36-specific addressees. The letter focuses on the following seven different areas involving 46 groups of questions (noted in parentheses): science/safety (11); regulatory/administrative (6); patents (6); exclusivity and other incentives (7); economic impacts (5); and European Union precedent (5). The sheer volume of possible replies suggests the utility of this initiative could be questionable, especially given the probable diversity of opinions.
A number of important new final guidance documents have recently been issued by the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), or both, pertaining to drug and other products of modern biotechnology. A final guidance on definitions of key terms in the areas of pharmacogenomics and pharmacogenetics covers these and other important terms, such as genomic biomarkers and sample coding categories. This document, entitled Guidance for Industry; E15 Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories (April 2008), follows up on a draft published in January 2007. It was developed under the auspices of the International Conference on Harmonization of Technical Requirements for Regulation of Pharmaceuticals for Human Use, which seeks to provide for tripartite harmonization among the European Union, Japan, and the United States. This guidance is available at www.fda.gov/cber/guidances.htm.
Two other final guidances pertaining to Chemistry, Manufacturing, and Control requirements for Investigational New Drug Applications involving either human somatic cell therapy or human gene therapy follow up on draft versions issued in August 2003 and November 2004, respectively. They are entitled Guidance for FDA Reviewers and Sponsors; Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs) (April 2008) and Guidance for FDA Reviewers and Sponsors; Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs) (April 2008). They can be found at the website referenced above.
A Canadian company recently publicly announced submitting an IND to FDA for recombinant human insulin produced in safflower, a crop that, unlike corn, apparently is not widely grown and does not present difficult issues of outcrossing with other plants. http://micro.newswire.ca/release.cgi?rkey=1607298075&view=36078-0&Start=0.
