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Clinically Meaningful Differences Under the Microscope


Clinical trials leading up to biosimilar approval may not reveal the full safety and efficacy profile of biosimilars vs reference products, and postmarketing studies may be essential to elucidate any differences, investigators said.

Editor's Note: Since publication of this article, the findings in the study by Rastogi S et al referenced below have been criticized as having been based on poor scientific methodology. Reliance upon data from the VigiBase adverse event database of the World Health Organisation, which is not intended for the testing of medical hypotheses, is one of the criticisms leveled against this study. The Center for Biosimilars® is preparing a follow-up article on this issue.

A recent postmarketing study suggests that certain filgrastim biosimilars lead to a higher incidence of certain adverse events, including back and joint pain, compared with the reference drug (Neupogen), although the products are considered to have no clinically meaningful differences.

The authors called some of the findings in the study “alarming” and concluded that “Clinical use outside the restrictive trial environment may be the only way to [determine] the safety profile of the drug.”

Postmarketing studies can play a meaningful role in determining the existence and significance of safety and efficacy differences between biosimilars and reference products, noted Sasha Bernatsky, MD, PhD, a rheumatologist, professor and senior scientist in the Centre for Health Outcomes Research and Division of Clinical Epidemiology at the Research Institute of McGill University Health Centre of Montréal, Canada.

Bernatsky is currently working on a 54-month rheumatology study of the comparative effectiveness and safety of biosimilars and legacy drugs.

Value of Postmarketing Studies

After marketing commences, studies are done to “determine if there are any safety signals that you hadn’t seen in the randomized control trials, because in the real world, we use drugs in a different population than [for clinical trials]. Any randomized control trial is usually conducted in a population that is maybe younger, has fewer comorbidities, and is a little different than what we see in the real world,” Bernatsky said.

However, postmarketing data may not always be the best way to assess real-world issues, she said. “If there are adverse effects occurring, patients and physicians are supposed to be reporting those, so that any safety signal can be detected. But we know that that those kinds of active surveillance systems may underreport adverse effects.”

Investigators in the study analyzing filgrastim biosimilars and increased adverse events noticed underreporting in Africa and Asia, which they attributed to poor follow-up surveillance. “Clinical trials are mandatory to evaluate efficacy but might not provide a definitive conclusion on safety of drug. This is partly because of limited patient exposure, marginal length of follow-up, and insufficient power to detect balances in rare adverse events,” the authors concluded.

“Our study results showed an alarming result regarding differences in efficacy, adverse events reported and their time to onset of occurrences among the originator and filgrastim biosimilars that needs further investigation. The reports of rare adverse reactions underscore the need for a more intense postmarketing surveillance of filgrastim biosimilars,” the authors wrote.

Bernatsky said that in her work, she has not encountered instances of approved biosimilars having clinically meaningful differences from reference products, and she remains comfortable using them in her practice. The weight of the evidence collected over time should help to clarify any differences between biosimilars and reference products, she said.

What Qualifies as Clinically Meaningful

“I believe that there’s a clinically meaningful difference when I’ve been able to show something statistically and in terms of the magnitude of the impact,” Bernatsky said. “If you have some kind of a statistical difference that is minimally impactful on the kind of outcomes that we’re looking for, for our patients, then that’s obviously not something that you would base a decision on [whether the biosimilar has a clinically meaningful difference to the originator drug].”

Bernastsky’s current study is designed to answer questions about safety and efficacy for biosimilars referencing etanercept (Enbrel) and infliximab (Remicade). The study is nearing its second year of investigation.

“Of course, we want to look at safety and all of the other outcomes that are important. But if you just look at this simple outcome of time on the drug, in the analyses we’ve done, we don’t see differences,” she said.

Studying the long-term use of a biosimilar can reveal why a patient discontinues treatment and whether safety and efficacy issues have something to do with it, Bernatsky said. However, the nocebo effect, which occurs when a patient’s negative expectations contribute to negative outcomes, along with other biases inadvertently introduced into studies, can cloud the picture on equivalence between biosimilars and reference drugs, and it is important to be on guard for those issues, she added.

“This project that we’re conducting right now is meant to be the pilot for hopefully, eventually, a very wide-scale initiative that could track the safety and effectiveness of biosimilars across a much larger spectrum—beyond rheumatology, gastroenterology, and across many more domains,” she said.

In her medical career, Bernatsky has had no compunctions about prescribing rheumatology biosimilars. Biosimilars actually have spillover benefits, such as savings that have enabled her and other clinicians to provide services to patients they couldn’t have received otherwise, such as physiotherapy and occupational therapy.

“For me, that’s a huge hole for my patients. Those who don’t have private insurance often don’t have good access to nondrug therapies that they really need. So, I’m really excited that this could be one of the positive offshoots of more use of biosimilars,” she said.


Rastogi S, Shukla S, Sharma AK, et al. Towards a comprehensive safety understanding of granulocyte-colony stimulating factor biosimilars in treating chemotherapy associated febrile neutropenia: trends from decades of data. Toxicol Appl Pharmacol. 2020;395. doi:10.1016/j.taap.2020.114976

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