Thus far, the EMA has received requests for scientific advice on six biosimilar antibodies, including one from Teva for a biosimilar version of Rituximab.
Regulatory guidelines will not be the same as those for licensing of less complex recombinants like somatotropins and erythropoietins. In November 2010, EMA released new guidelines on biosimilar antibodies for a five-month public consultation period.
It is expected that the EMA guidelines will contain requirements for clinical trials of biosimilar mAbs. As yet the regulations don’t spell out the extent of the clinical testing needed to establish biosimilarity. The agency has not said whether the biosimilar antibody would also be interchangeable with the original.
“We do not support interchangeability between an innovator biologic and a biosimilar product,” states current antibody producer MedImmune. At this time regulations allow generic versions of small molecule drugs to be dispensed interchangeably with the original product at the pharmacy, without the approval of a physician.
Early commentary on EMA guidelines acknowledges that coming up with a “general framework is a near-impossible task in this subject area due to the many differences from one mAb to the next.”
One common thread does exist in EMA’s guidelines—comprehensive risk planning at the early stages. The guidelines particularly focus on the problems manufacturers may experience with current assays used to assess mAb immunogenicity, stating that detection of antibodies against mAbs using ELISAs or radio-immunoprecipitation may not be adequate because of nonspecific binding. It notes that a new generation of assays with the requisite sensitivity for use in clinical settings needs to be developed.
In November 2010, FDA held hearings to obtain input on the implementation of the Biologics Price Competition and Innovation (BPCI) Act of 2009. The act established an abbreviated approval pathway for biological products that are demonstrated to be highly similar to or interchangeable with an FDA-licensed biological product.
The BPCI act currently provides for up to 12.5 years of nonpatent market exclusivity for a biological product approved under a BLA consisting of an initial 12-year exclusivity period that may be extended by 6 months of pediatric exclusivity.
Some other standards will likely pose challenges for antibodies, in particular the standard for interchangeability. To meet this criterion “A sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.” Since use of a biosimilar antibody could potentially preclude the use of the reference product in the same patient due to development of antiantibody antibodies, this regulation sets a high bar.
The guidelines are now open to public comment until May 31. Predictably, current manufacturers with products to protect took a fairly hard line on regulations for biosimilars in general. The Pharmaceutical Research and Manufacturers of America (PhRMA) along with some of brand-name drug makers told the FDA over the course of the two-day hearing that the science is “too lacking” at this point for the FDA to decide that some biosimilars are interchangeable with the original biologic.