Various countries have established legal and regulatory pathways to allow "copies" of an off-patent bio-therapeutic product
to be brought to market. However, unlike small-molecule generic drugs, these large, complex protein molecules cannot be absolutely
identical to the original. Instead, a large-molecule copy drug must be demonstrated to be similar to a reference product (RP)
by performing a side-by-side comparison to the originator molecule. There are many challenges—legal, regulatory, nonclinical
and clinical—that manufacturers must rise above to develop biosimilar products for global markets. Perhaps one of the first
hurdles is choosing the RP.
Fiona Greer, PhD
It has been nearly two years since President Obama signed the Patient Protection and Affordable Healthcare Act, which provides
for a regulatory pathway for biosimilar drugs through the Biologics Price Competition and Innovation Act (BPCIA) (1). The
European Union actually blazed the trail for biosimilars in 2005 when it established guidelines for "similar biological medicinal
products" (i.e., biosimilars) (2). Subsequently, Japan established guidelines on "follow-on-biologics" in 2009. Other countries,
including Brazil, Australia, Turkey, Taiwan, Malaysia, Argentina, Mexico, Canada, and South Africa followed thereafter with
many biosimilar regulatory pathways based on the EU model.
These national and regional guidelines do share a common theme: a step-wise, head-to-head comparability exercise between the
biosimilar in direct comparison with the originator requiring extensive physical, chemical, and biological characterization,
followed by nonclinical and clinical studies to demonstrate the same safety and efficacy profiles as the RP. All guidelines
state that the same RP should be used throughout the analytical characterization, nonclinical, and clinical study stages.
However, the specificity with regard to the selection of the RP differs among the various country guidelines.
For instance, many legal pathways, including those of the three leading members of the International Conference on Harmonization
(ICH) (i.e., the EU, Japan, and the US), require that the RP chosen is one which is already approved in the relevant country
or region of the application. The EMA guidelines state that the RP used must be authorized in the EU on the basis of a complete
dossier. Some data from comparability studies with a RP from outside the EU may be acceptable, but only for supportive purposes.
In the US, section 351(k) of the Public Health Safety Act, added by the BPCIA, requires comparison with a single RP which
has been approved under the normal section 351(a) with reference to prior findings on safety, purity, and potency. Interestingly,
the much anticipated recent (February 2012) draft guidances from FDA on both scientific and quality considerations in demonstrating
biosimilarity to a reference protein product do suggest a degree of flexibility (3). They state that in certain circumstances,
and with prior consultation, a sponsor may seek to use data derived from animal or clinical studies using a non-US-licensed
comparator product. However, in such cases adequate "bridging data" to a US-licensed RP must be provided. This topic is actually
discussed in detail in the accompanying Q&A document, in section 1.8 (3).
The World Health Organi-zation's Guideline on Evaluation of Similar Biotherapeutic Products, however, allows national regulatory authorities in countries without the particular approved product to accept a Reference
Biological Product (RBP) from another jurisdiction provided that it has a well-established regulatory framework (4). Looking
to Health Canada's guidelines, there is some flexibility in the source of the RP, provided that several conditions are met,
such as the product being from an ICH member country.
So, in effect, any biosimilar manufacturer who proposes to market its products globally—and there are several with this stated
aim—faces the prospect of multiple, separate studies that compare the biosimilar with different sourced RPs from the targeted
markets. Sourcing the appropriate RP material from one market alone is a difficult and costly exercise because multiple lots
manufactured over a long timeframe are required to establish changes in quality attributes.