Alicia Ault

April 07, 2015

With the first biosimilar approved by the US Food and Drug Administration (FDA) in March and a second approval likely in the next few months, practical and operational challenges are already starting, said experts at the American Pharmacists Association (APhA) 2015 Annual Meeting in San Diego.

A biosimilar is a "copy" of a commercially available biologic that has gone off patent. However, to receive approval from the FDA, the manufacturer of a biosimilar has to prove similarity in physiochemical characteristics, efficacy, and safety.

Biosimilars "have to be understood in a different way than the typical generic small-molecule drug," said James Stevenson, PharmD, from the University of Michigan at Ann Arbor. The manufacturing process is more complicated and can result in a somewhat different product in the end, "not like a generic, where you have a predictable chemical reaction that ends up with an identical active ingredient."

The generic company manufacturing a biosimilar has to demonstrate bioequivalence, but there is no single test to prove equivalence between the biosimilar and the reference product, Dr Stevenson told Medscape Medical News.

"The average community pharmacist may not have had contact with these medications," Jillanne Schulte, JD, director of regulatory affairs at the APhA, said during an interview. But they need to understand these classes of drugs, particularly for substitution issues, so they can educate patients, who are getting many messages about the relative safety of biosimilars.

One of the most challenging issues that pharmacists will encounter is the interchangeability of biosimilars and the reference product, she said.

Big Challenge Ahead

"The FDA has a very rigorous process to ensure that biosimilars are similar enough, so they don't expect there will be any clinically significant differences," Dr Stevenson said. However, the products, "by their nature, are going to be slightly different."

Biologics are derived from living cells or organisms and have larger molecules than chemically synthesized pharmaceuticals. They are complex and heterogenous and have molecular compositions that are hard to fully characterize. They also are unstable and immunogenic.

In the production of chemically synthesized pharmaceuticals, every unit made is an exact copy of the previous unit. However, with biologics, because of the complexities of manufacturing, there can be variations from one lot to another, Dr Stevenson explained.

In fact, changes in the manufacturing process can lead to a loss of potency, decreased protein stability, and potentially dangerous adverse effects, he added.

Biosimilars have been on the market in Europe for 9 years without any big safety issues, Dr Stevenson said. The experience is instructive because the FDA follows the same approval path as the European agencies. However, many European countries limit substitution and switching, he added.

The substitution picture in the United States is less clear right now.

The first biosimilar approved by the FDA — filgrastim-sndz (Zarxio, Sandoz/Novartis) — does not present as many challenges as other biosimilars in the pipeline might, said Dr Stevenson. It's usually prescriber-administered in the hospital, which makes it easier to track for safety. And, because there is a biomarker associated with efficacy — neutrophil count — "it's easier as a practitioner to feel comfortable interchanging," he explained.


The FDA will set rules on interchangeability, although this has yet to be done, but formulary committees will decide whether a biosimilar can be substituted for the reference product. So, for example, despite the FDA saying there can be no substitution, a formulary committee might decide that the two products are therapeutically equivalent, Dr Stevenson said.

The formulary committee will also have to decide whether a biosimilar is interchangeable for all the FDA-approved indications for the reference product, even if the biosimilar has not received those approvals.

The interchangeability of biosimilar monoclonal antibodies is even more complex, said Dr Stevenson. The first approval in that area — for palivizumab (Synagis, MedImmune) — could come later this year.

And although biosimilars might be less expensive to prescribe, there are concerns about setting up ordering, surveillance, and e-prescribing to keep track of which patients receive which products.

Tracking Glitches

"It's not good enough to know I gave a patient filgrastim, I have to know which filgrastim product they received," said Dr Stevenson. Although National Drug Code numbers can be used to track prescriptions in the community, those numbers are not always used in health systems, he pointed out.

These are practical scenarios we're be going to dealing with in the very near future.

"These are practical scenarios we're be going to dealing with in the very near future," he said.

The APhA is still talking with the FDA about naming issues, such as whether a unique name might cause problems with identification in some electronic health records, or cause confusion in prescribers, patients, and pharmacists, Schulte pointed out. The organization is waiting on the FDA guidance on interchangeability.

In the absence of FDA policy, many states are creating their own statutes. "Are these the same drugs? In many states the answer is no," said Schulte.

There are also unsettled debates about whether patients and prescribers should be notified of a substitution, and how, she said.

The states that have already approved legislation have generally prohibited or minimized interchange, Dr Stevenson reported. But the trend seems to be turning toward deferring to the FDA, he said.

Still, pharmacists could be in a tough spot if federal and state rules differ. Pharmacists should be aware of their state's laws, which could "govern their ability to have interchange," said Dr Stevenson.

Dr Stevenson reports serving as an advisor for Amgen. Schulte has no relevant financial relationships to disclose.

American Pharmacists Association (APhA) 2015 Annual Meeting. Presented March 27, 2015.


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