It was a pleasant surprise to see not one, but two recent commentaries on the subject of biosimilars in prestigious publications such as the New England Journal of Medicine (NEJM) and the Journal of Clinical Oncology (JCO). Given the novelty and complexity of biosimilars, new commentary in highly regarded clinical journals such as these is important to increasing the level of understanding and confidence necessary to boost adoption by clinicians.
The NEJM article is an overview of some of the key hurdles that have diluted the impact of biosimilar adoption. The JCO article introduced a position statement by the American Society of Clinical Oncology (ASCO), intended to provide guidance to the cancer care community regarding the role of these novel products. Both topics are highly relevant and expert opinion targeted at these issues is not just welcome, but desperately needed.
Unfortunately, included within the otherwise pertinent comments are statements either not entirely accurate or lacking the total context required to understanding biosimilars. These limitations could create unnecessary uncertainty for readers about biosimilars, making the task of creating a stable and competitive market of competing biologics more difficult to achieve.
Given that the subject of biosimilars is fraught with complexities, the following is a recap of those areas that I believe needed further clarification.
What is a biosimilar again?
This question may appear so basic, even asking it seems unnecessary. However, in both publications, basic descriptions and references add to confusion.
In the NEJM article, the author describes how, unlike generics, “physicians … do not have a clear understanding of biosimilar products.” That statement is definitely true. However, the author also comments that, “Physicians are naturally hesitant to prescribe biosimilars – especially given that regulations create the impression that a biosimilar may not be all that similar to its originator.”
The JCO position statement compounds this perspective when the authors state that, “Generally, FDA approval of a biosimilar product is an indication that safety and efficacy are not meaningfully different from the reference product.” [Emphasis added]
First, according to the FDA, “A biosimilar is a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product.” The both abbreviated and rigorous process of a biosimilar review is intended to yield a product that is highly similar to the reference biologic in terms of safety, purity and potency. If a biosimilar has been thoroughly vetted, as occurs in the U.S., we would fully expect it to behave in the same clinical manner as the originator.
Second, biosimilars approved in highly regulated markets like the U.S. and in Europe, have yielded the same clinical performance as their branded, originator counterparts.
This perspective has been repeated via FDA by education and communication, the publication of numerous guidance documents, and through the approval of nine biosimilars (only three are currently marketed in the U.S.).
The purpose and size of biosimilar clinical trials
Another aspect of the biosimilars concept that remains unclear for clinicians is the role and meaning of clinical trial data requirements. The JCO article notes it is unlikely that large, Phase III trials, will be conducted for all approved indications of the reference product. Statements like this one could raise alarms with clinicians.
The reality is that the absence of the need for large Phase III trials originates from the “stepwise” approach enumerated by the FDA, which again has been articulated in guidance documents and demonstrated in existing biosimilar approvals. Each step within the development process allows for following steps to be more targeted. As such, the resulting clinical trial(s) are usually small. Second, the principle of extrapolation allows for the evaluation of clinical performance in a certain indication to substantiate licensing across multiple indications of the originator biologic. This principle has been successfully applied to biosimilar approvals both in the U.S. and globally. As a result, it is not just unlikely that large Phase III trials will be conducted in every indication or the originator brand, it is unnecessary. And, clinicians can have confidence in the use of biosimilars approved through this mechanism.
Role of pharmacovigilance in biosimilar naming
The topic of biosimilar naming, which relates to pharmacovigilance, is another topic discussed in the NEJM article and which requires additional clarification. The article states that, “FDA guidance on biosimilar naming requires that each product include the nonproprietary name reflecting the active ingredient plus a suffix that identifies the manufacturer.” This is not an accurate portrayal of biologic naming.
While nonproprietary naming of biologics has been the subject of much conversation, the FDA has finalized its guidance on this subject and continues to license biosimilars, and even novel originator products, according to this stated approach.
The FDA has determined it will now use what has historically been described as the nonproprietary name, e.g., infliximab, as the “core name.” To this core, FDA will assign a four-letter, intentionally “devoid-of-meaning” suffix, e.g., infliximab-dyyb, forming what is now known as the “proper name.” This nomenclature has been applied to all biosimilar approvals following licensing of filgrastim-sndz and even for the most recently approved originator biologics. Per the FDA, all biologics will ultimately be subject to this naming structure, although the date of conversion for previously approved originator products remains uncertain.
Understanding this naming approach is important because clinicians must prepare for the presence of the devoid-of-meaning suffixes, which will not reflect a specific biosimilar’s manufacturer.
At the heart of the biosimilar approval process is the expectation that analytical techniques, combined with clinical data, can support licensing of safe and effective competing versions of commonly prescribed biologic drugs. Within this approach, there is a high commitment to accuracy of analysis. Just as the biosimilar approval process is based on accuracy, the way approved products are described also must be accurate. Due to the novelty of biosimilars, poorly articulated descriptions, even those that are inadvertent, can make acceptance and adoption by clinicians more complicated and limit opportunities for desperately needed competition and savings.
