Allan Gibofsky, MD

Allan Gibofsky, MD

Ask the Experts


Biosimilars in Rheumatology

Practice Community
New York, New York
Hospital and Institute Affiliations
Co-director, Clinic for Inflammatory Arthritis, Hospital for Special Surgery
Professor of Medicine, Weill Cornell Medicine


Question 1.

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


It is important to remember that the goal in biosimilar development is primarily to demonstrate that there are no clinically meaningful differences between products based upon what the US Food and Drug Administration (FDA) refers to as “totality of evidence.” The goal is not to re-establish the benefit of the biosimilar product, which has already been established by the originator product.

So, whereas standard biologic development begins with analytical testing, nonclinical testing, pharmacokinetic testing, and clinical trials, for a biosimilar the analysis of the drug analytical properties and pharmacokinetics is much more important in establishing the comparability of the biosimilar molecule to the bio-originator molecule. Remember: the biosimilar molecule has to be similar to the bio-originator product, but not identical.

Once the totality of the evidence has been demonstrated, usually with a head-to-head study of the biosimilar compared with the bio-originator, the FDA or European Medicines Agency will then review the evidence submitted by the biosimilar manufacturer. If approved, the molecule is deemed a biosimilar and can be used for all of the indications for which the originator is used, even if it hasn’t been studied for a particular indication. This concept is known as extrapolation.

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?


In my opinion, pharmacists should be required to notify prescribers and patients when indemnity plans and pharmacy benefit managers request automatic substitution of a branded biologic with a biosimilar because it’s important for a patient to know exactly what they’re getting. Substitution without the approval of the prescriber is called interchangeability and to date, no biosimilar has been deemed “interchangeable” by the FDA. In the event there is a problem, clinicians need to be able to identify the exact medication that caused the adverse event.

Thus, it would be problematic for a patient and for a prescriber not to know exactly what was given if the patient had an adverse event and required withdrawal from the agent.

It would also be problematic for the prescriber and patient not to know exactly what medication was given in the event that there is an increased number of adverse events that should be traced either to a particular lot or batch of a particular agent.

Question 3.

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


There are 2 time points at which the discussion will take place: for new starts of a biosimilar and for switches to a biosimilar.

With regard to patients starting a biosimilar for the first time, the discussion will largely focus on the risks and benefits of that choice of therapy. The patient should, however, be made aware that the major rationale for the use of a biosimilar is the reduced cost of the drug, because by definition the biosimilar offers no advantage in terms of efficacy and safety. It cannot. If it did, it would not be a biosimilar. So the patient needs to be aware that the agent being chosen — or in what I suspect will turn out to be most cases, the agent being mandated by the payer — is being mandated largely because of its cost, rather than any other factor.

Now with regard to patients who are already taking a brand-name biologic for whom there is going to be a mandated nonmedical substitution, those patients should also be made aware that the reason for this is a change in the cost of the drug acquired by their pharmacy benefits manager or plan.

A patient who is stable on a current bio-originator is a very different patient with a very different set of concerns than a new-start patient. And while it’s anticipated that new starts ought to be equivalent to the biosimilar in terms of outcomes, we really don’t have a lot of data on what will happen to patients who are switched, and what that will mean for clinical outcomes over significant periods of time.

Question 4.

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


If drug monitoring means clinical assessment or laboratory assessment, then there’s no reason to monitor a biosimilar any differently than how the bio-originator is being monitored, because the FDA has defined that with regard to efficacy, safety, potency, and purity. The biosimilar must have no clinically meaningful differences from the bio-originator.

Question 5.

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


Future clinical trials will largely be confirmatory, as the biosimilars have already been identified as safe and effective with no clinically meaningful differences from the bio-originators based on the totality of the evidence.

I’m not sure how many confirmatory clinical studies we’re going to see, since they’re really unnecessary given that the drug has been approved for the indications of the bio-originator. I think that safety and efficacy studies, if they do occur, will largely be “ho-hum,” further establishing what we already knew based on the studies that were submitted for approval.

Now what one might see is that if a biosimilar was studied in indication A and it is extrapolated based on indication to cover diseases B, C, D, and E, the manufacturer of the biosimilar might well do studies in B, C, D, or E in order to demonstrate efficacy in those particular disease states.

So I think that future clinical studies will be confirmatory of the totality of the evidence that was submitted to grant the original biosimilar approval.