Yusuf Yazici, MD

Ask the Experts


Biosimilars in Rheumatology

Practice Community
New York, New York
Hospital and Institute Affiliations
Clinical Associate Professor of Medicine, New York University School of Medicine
Director, Seligman Center for Advanced Therapeutics, NYU Hospital for Joint Diseases


Question 1.

What are important differences in biosimilar vs innovator reference product manufacturing, development, and approval?


There are key differences between biosimilars and the innovator reference product in manufacturing, development, and approval. In the United States, once a biosimilar has shown equivalence, mostly based on the chemical structure, biosimilar manufacturers do not have to go through every step that the originator drug went through to get approval. The point of distinction here is that these are not generic biologics — these are biologics themselves. They are just very similar — which is where the term “biosimilar” comes from — to an actual product.

This created some controversy when biosimilars came out because what ended up happening is that biosimilar manufacturers were able to expand drug labeling to include disease states the biosimilar was never studied in, based on the multiple indications for which the originator was already approved after similarity was shown for a single indication in a head-to-head trial. That is one of the main controversies currently.

In addition, biosimilar production has a shorter timeline, of course, because manufacturers do not have to do all of the phase 1, phase 2, phase 3, dose-finding, and dose-ranging studies that the originator drug manufacturers have done. Biosimilar manufacturers only have to show that their drug is similar enough to the reference product and must provide some clinical data that they are achieving outcome measures similar to those of the originator.

Question 2.

Should pharmacists be required to notify prescribers and patients when indemnity plans and pharmacy benefit managers request automatic substitution of branded biologics with a biosimilar?


I don’t think the pharmacist should be allowed to automatically substitute a biosimilar for a branded biologic, even though it will probably be okay for the majority of patients. We shouldn’t have a “one-size-fits-all” approach when dealing with health care, especially for serious diseases like rheumatoid arthritis and serious drugs like the biologic agents.

This has created controversy because it is one more area where a physician’s autonomy is curtailed by the insurance company, pharmacist, or pharmacy benefit managers who seem to be making these important decisions.

I should note that biologics and biosimilars have been around much longer in multiple European countries than in the United States. Those countries, including Norway and Denmark, have been keeping track of how their patients have been doing when they have automatic biosimilar substitution. They found no differences in clinical responses where the patients are automatically switched over to the biosimilar, at least in the groups of patients they looked at.

However, that doesn’t give me a lot of comfort because physicians do not treat groups of patients. We treat individual patients. And every patient is different from another, especially given the other drugs that they may be taking. So it is very difficult to predict how a patient will respond to a drug as far as drug-drug reactions.

The originator biologics went through a lot more studies in a lot more different types of patients, which allows us to better fine tune a more individualized treatment and decide which biologic is better for what type of patient. We don’t have that data yet for biosimilars. That is why many physicians in the United States are up in arms about these automatic substitutions.

Question 3.

How should clinicians approach discussions regarding biosimilar interchangeability with their patients?


Clinicians need to let their patients know what their concerns are with switching to a biosimilar. This may include apprehension that the same therapeutic response may not be attained in the first place, or that the side effect profile is different when using a biosimilar vs a brand name biologic. Clinicians and patients should be more vigilant with monitoring when these switches are made, with special attention focused on side effects and not achieving the expected response that we would have had with an originator product.

Question 4.

Will therapeutic drug monitoring practices be changed with the adoption of biosimilars?


I do think therapeutic drug monitoring practices will be changed with the adoption of biosimilars. Let’s say a patient is started on the adalimumab reference product and then switched to an adalimumab biosimilar. This patient should be treated as if a completely new drug has been started, with laboratory and other testing intervals as if they have been started on a new drug. For example, if you are testing a stable patient using the biologic reference product every 3 months, you may go to testing every 4 weeks when switching to a biosimilar, at least initially, to make sure that there are no new safety issues.

Question 5.

What role will future confirmatory clinical studies have in validating biosimilar safety and efficacy?


Post approval studies, phase 4 studies, are especially important for biosimilar products. All of the originators, as part of their approval packages, have had at least 10 years of follow-up studies either with new cohorts or with the patients who were taking part in the initial reference product approval process. So we have a very good idea of what happens to patients on etanercept after 10 years, adalimumab after 10 years, and infliximab after 10 years. This is not true for biosimilar products. There is no requirement for biosimilars to do the same, but there should be.