Biosimilars in the US & EU Regulatory Pathways

In early November, the Food and Drug Administration held a two-day public meeting to gather input from a variety of industry stakeholders to determine the future of a regulatory pathway for biosimilar development in the United States. Later in the month, the European Medicines Agency issued its draft guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use, available at www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/11/WC500099362.pdf.

In a recent interview with Applied Clinical Trials, Jeffrey Freitag, MD, Senior Vice President of PharmaNet, offered his thoughts on the future of biosimilar development in the United States, as well as how the EU's more advanced regulatory pathway impacts this side of the pond.

"The big unknown is really what's on the horizon and that is the monoclonal antibodies. Blockbuster monoclonal antibodies primarily in the cancer arena and rheumatology are going to be coming off or already are off patent," said Frietag. In a related statement released by PharmaNet, he stated that for the FDA moving forward, immunogenicity or patient safety will "emerge as the key issue and that carefully designed clinical trials will be crucial in this process."

At the FDA meeting, Freitag said that some presentations keyed in to "very interesting" concepts of trial designs. "I think that is what is likely going to be required as we go forward—especially with monoclonal antibodies—is innovative trial designs. And that can take many facets," said Freitag.

He believes it will require the cooperation between clinical developers and the regulatory agencies to come up and approve these innovative designs. Those novel designs could take the following forms: use of surrogate endpoints; shortened time intervals for approval with follow-on later after approval, for example as in oncology drugs; innovative statistical methodologies; and others. Freitag said "something is going to need to be considered if you want to avoid having to do many, many hundreds, if not thousands of patients in an equivalence design clinical trial."

To date, Europe has approved 14 biosimilars with no significant safety issues reported (save for one that was a follow-on biologic called Eprex, an epoetin alfa to treat anemia, which suffered from a significant safety issue in France). The biosimilar developments that have been reviewed in Europe include three classes—human growth hormones, epoetins, and recombinant insulins. Freitag noted that these drugs have been fairly safe and that was supported by the audience when the FDA asked if there were any issues they should be alerted to and no one responded. "Meaning that the European experience has been a positive one," Freitag said. "And that the follow-up to that was would the FDA consider letting data from Europe carry the weight of the necessary approval process for US submissions. So I think that remains out there as potential consideration."

Freitag emphasized that the FDA is not going to follow the European Guidelines, per se. However, because there has been several years of use of biosimilars in the EU, with exhaustive review and without safety issues, it might make sense to not reinvent the wheel and allow some use of the clinical data in the United States.

Sponsors desiring a formal biosimilar guidance from the FDA will go forward without, as Freitag noted in the podcast interview available on the Applied Clinical Trials website. With a growth hormone already approved in the United States, as well as the July 2010 FDA approval of a low-weight molecular heparin (enoxaparin), there are pathways to approval.

In fact, according to Freitag, the enoxaparin approval may offer an inkling of where the FDA and Europe differ. "Enoxaparin was approved in the United States earlier this year based on preclinical data and Phase I data and no late phase clinical trials. Europe would suggest, based on their guidelines that late-stage trials will be necessary. In fact, Europe has more or less stated, even though they have developed a guideline for low molecular weight heparin, they feel it is very unlikely that a biosimilar for low-weight molecular heparin...could be approved in Europe just because of the difficulties in demonstrating biosimilarity."

What does this mean to the clinical trial community? Obviously, says Freitag that there wouldn't be inappropriate short cuts taken in clinical development. However, clinical trials will be impacted by taking European data into consideration, as well as innovative trial designs and ethical concerns surrounding any patient population.