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First biosimilar drug approved for sale in the United States

New options for biologic cancer treatment are coming for the first time to the United States, and their arrival could help drive down costs for some of the biggest-ticket items in cancer care.

Treatments that interfere with cancer’s biological underpinnings have revolutionized treatment for some cancers. But their cost now accounts for half of oncology drug spending—up from 11% a decade ago, according to the IMS Institute for Healthcare Informatics.

Biosimilar drugs, close copies of patented biologicals, have been available in Europe for nearly a decade and can cost up to one-third less than their patented counterparts. The competitive principle is similar to that of well-known generics, but since drugs manufactured in living organisms tend to be large, complex molecules that can’t be duplicated precisely, they have been labeled biosimilars.

The US Food and Drug Administration had been slow to follow Europe’s lead. But the Biologics Price Competition and Innovation Act of 2009 began to speed up adoption of these agents and offer competition in the health care marketplace. With a framework for adoption in place, FDA in early March 2015 approved Sandoz’s filgrastim-sndz, a biosimilar of Amgen’s filgrastim, which counteracts chronic neutropenia by stimulating production of immune system–boosting white blood cells. Although filgrastim is classified as supportive treatment, other mainstays of cancer treatment will soon lose their patent-protected status in the United States. The patent on trastuzumab, the hugely successful targeted monoclonal antibody therapy for HER2-positive cancers, expired in Europe mid-2014; the US patent expires at the end of 2018. Trastuzumab biosimilars from at least four companies are completing phase III clinical trials and are expected to be approved by the European Medicines Agency within months.

Whether biosimilars will help lower the price of biologics is an open question that may depend, at least initially, on oncologists’ willingness to prescribe them. Most oncologists are not aware of biosimilars. Even if they have heard of the term, they are confused about how biosimilars relate to more familiar brand-name drugs, according to Andrew Zelenetz, M.D., Ph.D., a medical oncologist at New York’s Memorial Sloan–Kettering Cancer Center. Zelenetz chaired the committee that wrote a 2011 white paper on biosimilars commissioned by the National Comprehensive Cancer Network.

A 2011 survey of oncologists attending the annual National Comprehensive Cancer Network conference revealed that more than half of respondents were either not at all familiar (36%) or were only slightly familiar (19%) with biosimilars. But interest is high, with 27% and 35% responding high and moderate interest, respectively, in prescribing them.

Not much has changed since then, according to Zelenetz. He said even his colleagues at academic medical centers are not clear what biosimilars are. But he expects that to change shortly, when pharmacy formularies and payers start exerting pressure to prescribe these drugs, which will probably have lower prices. In Europe and elsewhere, biosimilars are routinely priced 20%–30% less than the original drug.

Price Pressure

Many questions about the niche biosimilar products will fill remain unanswered. Unlike generic drugs, biosimilar products are unlikely to be automatically substituted at the pharmacy level, at least initially. That would require the product to be deemed interchangeable with its counterpart, and FDA has yet to issue firm guidance on interchangeability standards. Unless institutional pharmacy and therapeutics committees can make automatic substitutions, a delay may occur before people see cost savings from biosimilars, according to Zelenetz.

Even the definition of how similar a copy of a biological drug need be is not set. That’s the “million-dollar question,” said Leah Christl, Ph.D., FDA’s associate director for therapeutic biologics. “A sponsor can’t use a clinical study to compensate for a lack of analytical similarity.”

Conversely, if a product doesn’t share a safety and toxicity profile with the originator drug, it doesn’t meet the biosimilar bar, and can’t claim to be a biosimilar, she said.

Process is Product

Biosimilar products start with essentially the same genetic sequence. But they are produced in living cells, and the particulars of those production processes are guarded trade secrets. Because of the vagaries of biological systems, differences in cell culture systems can influence the product. That’s why FDA pays as much attention to the manufacturing process as to the product.

“It is a challenge to run a complex manufacturing process for biopharmaceuticals,” said Stephen P. Creekmore, M.D., Ph.D., chief of the Biological Resources Branch at the National Cancer Institute. “There is a risk to using these products, and the FDA is trying to minimize the risk to make sure the biosimilar is as close to the reference product as they can.”

Even if a manufacturer can show that a product meets the FDA standard for biosimilarity, some oncologists may be concerned about extrapolation, Zelenetz said. FDA states that a biosimilar must show analytical comparability to the US licensed reference product but might not require full clinical trials for all indications.

“From an ethical standpoint—and the European Medicines Agency and the FDA share this—we don’t want companies to have to repeat clinical trials, so we have established a scientific approach that both entities have adopted in order to support global development,” Christl said.

In practice, that may mean companies conduct a trial in what FDA calls the most sensitive population. But the definition of “most sensitive” may be left up to the company. For instance, several companies are in phase III clinical trials to compare biosimilars of rituximab with its patented reference product in rheumatoid arthritis patients. But if these products become licensed in the United States, oncologists may not be comfortable prescribing them for lymphoma, Zelenetz said.

Many oncologists may want to see direct comparator trials, Creekmore said. “And I would talk to colleagues about their experience with it, just to be a little cautious.”

Note: Zelenetz is on the biosafety monitoring board for a company developing a biosimilar, but he has no financial stake or stock in any company and is conducting no clinical trials on any of these products.

A version of this blog post first appeared in Journal of the National Cancer Institute.

Image Credit: “The Morning Handful” by Derek K. Miller. CC BY NC 2.0 via Flickr.

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