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FDA laid out its basic approach for biosimilar development in three draft guidance documents published in February 2012, and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.