Biosimilar Lessons From The EU

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

The European biosimilar market is leaps and bounds ahead of the U.S. market, though the levels of uptake and experience certainly vary from country to country depending on their individual policies and prices. As the FDA begins to solidify its naming, labeling, and interchangeability policy, it’s informative to consider how European countries have addressed the same policies. In her presentation at the recent GPhA conference, Suzette Kox, the senior director of the Biosimilars Medicines Group and chair of the biosimilars committee of the International Generic and Biosimilar Medicines Association, offered the European perspective on several topics that are currently being debated in the U.S.

The EMA’s “Living” Biosimilar Guidelines

I recently wrote an article discussing what regulatory flexibility means to both the European Medicines Agency (EMA) and the FDA. A study published in the British Journal of Clinical Pharmacology (BJCP) determined the biosimilars reviewed by the EMA all differed in terms of their development programs, even though they were biosimilars of the same reference product. The FDA is still in the process of drafting guidance on statistical analysis standards for determining biosimilarity. However, at the recent GPhA Leading On Biosimilars Conference, the FDA spoke at length on the human aspect of regulation and the room for flexibility in the biosimilar evaluation process.

Though the EMA has issued a number of biosimilar guidelines, “These are living documents,” Kox emphasized. “Companies can always come with new approaches to development. This is important for companies to acknowledge, because if you make your case, and the science is strong, your work and input may be reflected afterward in the guidelines.” The study in the BJCP is a prime example of this, as the authors determined the biosimilars approved didn’t always follow the EMA’s product-specific guidelines. The application simply had to be “convincing.”

Manufacturing Changes Important In Switching Debate

It’s been reiterated many times that, like biosimilars, the reference biologics have slight differences from batch to batch. Steinar Madsen of the Norwegian Medicines Agency stated it best when he said, “Biologics are all biosimilars.” According to the EU definition, a biosimilar must contain a version of the active substance of the reference product. As Kox stated, “I think this is interesting wording.” Indeed, this definition highlights the complicated nature, or life cycle, of biologic drugs. For instance, it’s normal that biologic drugs would undergo small changes after approval because of improvements in manufacturing processes.   

In Sandoz’s Enbrel biosimilar FDA advisory committee meeting, Mark McCamish, the company’s global head of biopharmaceutical development, showed the committee a slide of the various changes to Enbrel’s manufacturing process. Obviously, none of these changes were found to be significant enough to disqualify the molecule from treating all indications.

Manufacturing changes were also a key topic in Kox’s presentation. Several panelists at the conference, including Kox, highlighted a 2013 publication by Dr. Christian Schneider. In his article, Schneider emphasized the manufacturing changes originator monoclonal antibodies undergo, which lead to slight differences between batches.

“All of these manufacturing changes have been approved, and there have been no issues,” Kox described. “The point to take away here is the INN [international nonproprietary name] always stayed the same. The label also stayed the same. The previously approved safety and efficacy data was also applicable to the new version of the active substance.” In other words, there will always be different versions of the same active substance on the market, whether it be a biosimilar or an originator.

The industry regularly encounters resistance to switching to a biosimilar and concerns about immunogenicity. Hence, it is important to bring up manufacturing changes and “broaden this debate,” Kox said. “We shouldn’t only be focused on biosimilars. After all, the science and scientific approach is the same between biologics and biosimilars.”

Why U.S., WHO Naming Policies Concern Europe

One of the most powerful quotes in Schneider’s article zeroed in on the language we use to discuss biosimilars today. “The sentence ‘biosimilar and biological reference medicines are similar but not identical is perhaps one of the most frequently misunderstood sentences in the history of biosimilars…,” Schneider writes. Indeed, this phrase has been the basis of many arguments in the burgeoning U.S. market that biosimilar naming and labeling should be different from that of the reference drug. In her presentation, Kox expressed her firm loyalty to the naming system that has been in place in Europe since the beginning.

In Europe, biosimilars share the same INN as the reference product and are not required to have a random four-letter suffix. After all, the INN is supposed to identify the active substance within the drug, rather than the drug as a whole. Similarly, in the EU, prescribers typically only use the INN to prescribe small molecule generics, as biologics are prescribed by brand only. As Kox said, “We have happily used the same INN in Europe, and it has been successful.”

One of Kox’s biggest concerns about the FDA’s current naming policy is that it is not aligned with the International Organization For Standardization (ISO) for the identification of medicinal products (IDMP). The ISO IDMP is a set of global standards dictating the data, formats, and terminologies needed to properly identify medicines. The standards were developed by regulators throughout the world and were published in 2012. They are currently being implemented in the EU, and the FDA is also in the process of ISO IDMP implementation. As Kox described, “These standards have been developed to establish a lasting framework which allows for the exchange of medicinal product information across regulatory and healthcare communities.” The suffix on biosimilar names in the U.S. will not be easily identified or relevant in the nations outside of the U.S.   

Kox also expresses concern about the WHO’s naming policy, as it “endangers the valuable INN system.” She quoted part of a WHO resolution on the INN, which charges member states to “enact rules or regulations to encourage manufacturers to rely on their corporate name and the INN to promote and market multisource products introduced after patent expiry.” (Think, for instance, of Epoetin Alfa HEXAL, which combines the active ingredient and the company name. This strategy is generally employed in the EU when a biosimilar has no invented name.) Judging from the latest WHO biosimilar naming suggestion, which includes not only a suffix but a two-digit checksum, it’s clear the WHO has been swayed from the resolution Kox quoted.   

The EMA has approached some of the same trials the FDA is confronting today. As we’re currently seeing, the U.S. has chosen to approach some of the policies, like naming and interchangeability, in its own unique and (to some, controversial) way. Though Kox expressed big concerns over the FDA naming policy, her presentation overall highlighted some of the positive directions in which the industry is moving. Between the documentation of biologics manufacturing changes and regulatory flexibility, the industry certainly has some great support to further its biosimilar educational mission.