Are interchangeable biosimilars better?

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How similar are biosimilars to their branded “mains”? This is an issue that continues to plague biosimilars and hinder their acceptance in everyday healthcare. Congress and the FDA may have unwittingly fueled doubts by creating the interchangeable designation. Some manufacturers argue that there is a perception, fostered by manufacturers of interchangeable biosimilars and their marketing tactics, that interchangeables are somehow “better biosimilars”.

Biosimilars are certified by drug regulatory agencies, such as the FDA in the United States and the European Medicines Agency in Europe, to be as safe and effective as their reference products. Interchangeable biosimilars are no different from biosimilars, except that when a doctor prescribes an originator biologic, pharmacists can give the patient an interchangeable biosimilar without having to see the doctor, subject to state laws.

Adding to the confusion is that interchangeable biosimilars undergo switch studies to ensure that patients switching back and forth between the original agent and the interchangeable agent will experience no difference in outcomes.

Companies such as Alvotech and Biocon Biologics use the interchangeable designation as a marketing ploy to differentiate their biosimilars from others. The tactic is a concern for manufacturers such as Samsung Bioepis who have opted to create regular biosimilars without the interchangeable designation.

“There is an increasing urgency for the semantics to be clarified,” said lead authors Joseph P. Park, Ph.D., senior director of regulatory affairs for Samsung Bioepis, and Gillian Woollett, MA, vice president and chief corporate strategy and regulatory policy. , wrote in an opinion piece published in Biodrugs in June. Their central argument is that interchangeability “is a legal distinction, not a clinical distinction”.

The other authors of the piece also work for Samsung Bioepis, which has a major interest in the interchangeable debate. The South Korean company has developed a biosimilar to Humira (adalimumab) called Hadlima (adalimumab-bwwd) which is not designated as interchangeable.

The question of interchangeability will come to a head next year when the market for Humira is flooded with biosimilars, both interchangeable and regular. No less than 11 Humira biosimilars could enter the market in 2023.

Marketing appeal

Although interchangeable products can be substituted more freely over the pharmacy counter, physicians (not pharmacists) can still substitute regular biosimilars as they wish and use them as directed by the FDA or off-label. “For each FDA-cleared biosimilar, physicians and their patients can have as much confidence as they have historically had with the originator product,” Park and Woollett wrote in Biodrugs.

Interchangeables haven’t been around that long. Semglee (insulin glargine-yfgn) was approved as the first interchangeable biosimilar in July 2021. Biocon Biologics specifically sought this designation so it could rebrand Semglee and enhance its marketing appeal.

Boehringer Ingelheim’s Humira biosimilar, Cyltezo (adalimumab-adbm), received an interchangeable designation in October 2021, and Alvotech, an Icelandic company, may get one for its Humira biosimilar, named AVTO2 for now. The FDA is currently reviewing the company’s application for AVTO2, and the biosimilar could hit the market in mid-2023. This would pit two interchangeable Humira biosimilars against the rest of the Humira biosimilars field, although Pfizer, Amgen and Samsung Bioepis have also said they also intend to seek interchangeability status for their biosimilars. Because they come to market in the same year, the market for Humira biosimilars in 2023 and beyond will be a good test of whether the interchangeable designation will be an advantage for biosimilars.

Interchangeability in other countries is not an additional regulatory distinction, according to Park, Woollett and their colleagues. “European Union regulators have said they consider all of their approved biosimilars to be clinically interchangeable,” they wrote.

North of the border

Public health authorities in Canada, impatient with the slow uptake of biosimilars, have forced patients to switch to biosimilars unless their physicians obtain medical exemptions. Canadian officials consider biosimilars to be equal to reference products, period, and therefore the issue of interchangeability is moot.

As the Canadian experience has shown, physicians may be hesitant to adopt biosimilars, and many tend to wait for as much clinical data as possible. This trend gives an advantage to companies that invest in additional switch studies so that their biosimilar can qualify for an interchangeable designation.

However, many biosimilar experts claim that the comparability of biosimilars to reference products is best demonstrated by analytical testing, such as pharmacokinetic and pharmacodynamic laboratory studies. Clinical studies conducted with human subjects are less accurate, they say. Sometimes biosimilar studies conclude that biosimilars are not always close copies of the reference products. Sometimes these differences are attributed to the nocebo effect – when people experience adverse effects and other negative consequences from a drug (or placebo) that they believe is inferior or potentially harmful.

A study published in the journal Health and skin diseases end of 2021 will not help the arguments of those advocating for biosimilars. The results showed that patients who switched to the Humira biosimilar Amjevita (adalimumab-atto) were more likely to have exacerbated symptoms of psoriasis. The authors wrote that 30% of patients receiving Amjevita had increased psoriasis severity and reduced quality of life. They said results returned to normal when patients restarted Humira.

However, the study was retrospective, single-center, and unblinded, which cast doubt on the validity of the results. Amjevita, an Amgen product, is expected to be the first Humira biosimilar to hit the US market in 2023. It does not have the interchangeable designation.

The FDA has worked to educate the public about the differences between biosimilars and interchangeable biosimilars, and more guidance is underway. Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars at the FDA’s Center for Drug Evaluation and Research, described some of the agency’s plans at a conference in late 2021. She said that manufacturers also need help understanding what happens to interchangeable designations when the mode of administration changes. Such changes could raise questions about whether the interchangeable biosimilars are still interchangeable with the reference products if the reference products are delivered in another way.

Tony Hagen is a medical, business and environmental editor and writer in Florence, New Jersey.

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