Recognition Is Nice, But Accuracy Is Most Important When It Comes to Biosimilars

It is always appreciated when contributions are made to the clinical literature concerning biosimilars. Given the novelty and complexity of this topic, additional commentary remains a necessity to reinforce key aspects of the biosimilar paradigm and offer the most up-to-date perspectives on how to expand uptake. As a result, it was a pleasant surprise to see not 1, but 2 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).^1,2 The first publication offered an overview of some of the key hurdles that have thus far diluted the impact of biosimilar adoption.¹ The second reference 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.²

Both topics are very relevant. Biosimilars have had to endure many roadblocks as they struggle to achieve equivalent footing with originator biologics. Also, multiple oncology-related biosimilars, including competing versions of pegfilgrastim and various monoclonal antibodies, could enter the market between late 2018 and mid-2019.³ As a result, expert opinion targeted at these issues is not just welcome, but desperately needed.

Unfortunately, included within the otherwise extremely relevant comments are statements not completely accurate, or lacking the full detail needed to understand key concepts, which could inadvertently create greater uncertainty about biosimilars. If the commentary we offer to improve the poor comprehension about biosimilars itself contains errors or a limited appreciation of the approval framework, the task of creating a stable and competitive market to reduce pharmaceutical expenses becomes that much more difficult. As a result, this update is intended to illustrate those areas where a more accurate assessment is required.

What Is a Biosimilar Again?

For those who have followed the development of biosimilars, this question may appear so foundational that even asking it appears irrelevant. However, in both publications mentioned above, it is clear that basic nomenclature still lacks comprehension among stakeholders. In the NEJM article, the author describes how, unlike physician attitudes toward generics, “physicians…do not have a clear understanding of biosimilar products.”¹ 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.”¹

The JCO position statement further compounds this perspective when the authors write that, “Generally,” the Food and Drug Administration’s (FDA), “…approval of a biosimilar product is an indication that safety and efficacy are not meaningfully different from the reference product.”² 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.”⁴ The end result of the approval process is a product that is highly similar to the originator.⁴ There is no other interpretation of the conclusion and this endorsement is not a “general” assertion. The totality of the approval effort (analytical characterization, pharmacokinetic and pharmacodynamics studies, immunogenicity testing, and phase 3 clinical trial data) is intended to substantiate this determination.⁴ This perspective has been repeated by the FDA via education and communication, the publication of numerous guidance documents, and the approval of 9 biosimilars, only 3 of which are marketed (the NEJM article incorrectly states that 7 biosimilars are presently on the US market).^1,4-6 As such, the overarching, scientifically justified conclusion is that an FDA-licensed biosimilar will be expected to behave similarly to the originator against which it is compared.

The Purpose and Size of Biosimilar Clinical Trials

Other aspects of the biosimilar concept that remain murky for some are the role and meaning of clinical trial data requirements. The JCO article includes the comment that the “FDA approval process for biosimilars makes it less likely that large, phase 3 trials will be undertaken for all approved indications of the reference product.”² The presence of large phase 3 trials for all indications of the originator is not just an unlikely occurrence, it is an outcome guaranteed not to transpire.⁷

The absence of the need for large phase 3 trials originates from the “step-wise” approach enumerated by FDA, which again has been articulated in guidance documents and demonstrated in existing biosimilar approvals.^6,8 Each step within the development process allows for the following sequences to be more targeted and focused. As such, the resulting clinical trials are usually small in size.

Second, the principle of extrapolation allows for the evaluation of clinical performance in a certain indication to justify licensing across multiple indications of the originator biologic.⁸ This principle has been successfully applied to biosimilar approvals both in the United States and globally.⁷

Role of Pharmacovigilance in Biosimilars

The intensity and processes by which pharmacovigilance for biosimilars should occur are also discussed within these 2 articles.^1,2 In the ASCO position statement, the authors write that “Given that regulatory review of biosimilars, compared with reference products, relies less on clinical data and more on structural, functional, and pharmacologic data, there will be a greater reliance on postmarket evidence development to demonstrate the value of these products to stakeholders.”²

There are several issues with this statement. First, 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.^7,8 If a biosimilar has been thoroughly vetted, as occurs in the United States, we would fully expect it to behave in the same clinical manner as the originator.

Second, the biosimilars that have been approved in the United States and the many more that are licensed in Europe have yielded the same clinical performance as their branded, originator counterparts.⁹ This understanding does not render pharmacovigilance unnecessary, as adverse events can and will occur. However, all pharmaceuticals, small molecule and biologic, brand, generic, and biosimilar, should be subject to appropriate and accurate pharmacovigilance.

Along the same lines, the topic of biosimilar naming, which relates to pharmacovigilance, is also discussed in the NEJM and requires additional clarification.¹ In the NEJM perspective, the author 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.”¹ This is not an accurate portrayal of biologic naming.

While nonproprietary naming of biologics has been the subject of much conversation, FDA has finalized its guidance on this subject and continues to license biosimilars and even novel originator products according to its stated approach.^6,10 The NEJM article cites the example of the first licensed biosimilar, filgrastim-sndz. However, at the time of initial approval, the FDA stated that the “-sndz” suffix was part of a provisional name.¹¹

Since then, FDA has crafted a different approach under which what has historically been described as the nonproprietary name (eg, infliximab) is now known as the “core name.”¹⁰ To this core, FDA assigns a four-letter, intentionally “devoid-of-meaning” suffix (eg, infliximab-dyyb) forming what is now called the “proper name.”¹⁰

This nomenclature has been applied to all biosimilar approvals following the licensing of filgrastim-sndz, and even for the most recently approved originator biologics.⁶ Per FDA, all biologics will ultimately be subject to this naming structure, although the date of conversion for previously approved originator products remains uncertain.¹²

This distinction is important because, while having the suffix related to the supplier might technically make pharmacovigilance easier, it is not the manner FDA has chosen for differentiation of biosimilars from one another and from their originator reference counterparts. Clinicians within healthcare organizations must prepare for the presence of the devoid-of-meaning suffixes and not rely on them to refer to a specific biosimilar’s manufacturer.

Conclusion

At the heart of the biosimilar approval process is the expectation that analytical techniques combined with an appropriate application of clinical data can support licensing of safe and effective competing versions of commonly prescribed biologic drugs. Within this methodology is a high commitment to accuracy of analysis. Just as the biosimilar approval process is based on accuracy, the way in which we describe this mechanism, and the approved products that result from its application, must be similarly accurate. Due to the novelty of biosimilars, incompletely articulated descriptions, even those that are inadvertent, will make acceptance unnecessarily more complicated and limit opportunities for desperately needed competition and savings.

References

1. Frank RG. Friction in the path to use of biosimilar drugs. N Engl J Med. 2018;378:791-793. doi: 10.1056/NEJMp1714908.

2. Lyman GH, Balaban E, Diaz M, et al. American Society of Clinical Oncology Statement: Biosimilars in Oncology. J Clin Oncol. 2018 Feb 14 [Epub ahead of print]. doi: 10.1200/JCO.2017.77.4893.

3. IPD analytics database. www.ipdanalytics.com. Accessed March 13, 2018.

4. Biosimilar and Interchangeable Products. FDA website. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm580419.htm. Accessed March 13, 2018.

5. Biosimilars. FDA website. https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm. Accessed March 13, 2018.

6. Drugs@FDA: FDA approved drug products. FDA website. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed March 13, 2018.

7. Weise M, Bielsky MC, De Smet K, et al. Biosimilars: what clinicians should know. Blood. 2012;120:5111-5117. doi: 10.1182/blood-2012-04-425744.

8. Scientific considerations in demonstrating biosimilarity to a reference product. FDA website. https://www.fda.gov/downloads/drugs/guidances/ucm291128.pdf. Accessed March 13, 2018.

9. Cohen HP, Blauvelt A, Rifkin RM, Danese S, Gokhale SB, Woollett G. Switching reference medicines to biosimilars: a systematic literature review of clinical outcomes. [Published online March 3, 2018] Drugs. doi: 10.1007/s40265-018-0881-y.

10. Nonproprietary naming of biological products. FDA website. https://www.fda.gov/downloads/drugs/guidances/ucm459987.pdf. Accessed March 13, 2018.

11. First US biosimilar launch. Nat Biotechnol. 2015;33:1013. doi:10.1038/nbt1015-1013b.

12. Bechtel J. Proposed rule would change names of six biologicals, including Neupogen. FDA News website. https://www.fdanews.com/IPRM0916152. Accessed March 13, 2018.