Evaluation of biosimilars

Biosimilars, biologic drugs that are “highly similar” to licensed reference products, come with a promise from United States and European regulatory authorities to reduce costs and increase patient access, although it remains to be seen whether this will be the case. In this video, Dr Bruce Strober discusses topics covered by 2 recently published manuscripts, written on behalf of the International Psoriasis Council, that focus on the preclinical and clinical requirements for the approval of biosimilars.

My name is Bruce Strober and I'm from the University of Connecticut. I’m the Professor and Chair in the Department of Dermatology there and today we're going to discuss two papers (manuscripts) published by Dr Andrew Blauvelt on behalf of the International Psoriasis Council. These papers address the topic of biosimilars. Now whether you want to accept it or not, biosimilars are here to stay. Biosimilars are a mandate from both the US and European authorities, which holds a promise: the promise being lowered costs for biologic therapies (for example therapies for psoriasis) and, as well, better access—of course lower costs might lead to better access. Now whether those promises will be delivered in the long run is left to be seen and it's really a topic for another day. What I want to discuss with you are the topics brought up by these manuscripts, particularly the preclinical testing and the clinical testing that underpins approval for biosimilars.

So important points about biosimilars that you need to recognize: biosimilars are not identical replicas of the reference product. Reference product being, for example, Enbrel or Humira or Remicade. Biosimilars are comparable; they are neither better nor worse. So no-one’s going to tell you (particularly the company that makes a biosimilar) that their drug is better or worse than the reference product, they’re just going to tell you they are comparable. And in reality the FDA and the EMA only look for a totality of data, both at the preclinical and clinical level, that justifies the statement that a biosimilar is comparable. It's really impossible to make an identical replica to a very complex 150 kilodalton monoclonal antibody. The sequence is duplicated, the post-translational modifications are attempted to be comparable, but identity is really an impossibility. And really the best way to think of a biosimilar—if it meets all the criteria set out by the regulatory authorities—is it's like another lot of the reference product. It's not identical and lots vary over time. But in reality the lot differences (the small differences that may be present) really have no clinically meaningful differences from the reference product in terms of both safety and efficacy and immunogenicity, and in pharmacokinetics. You basically have what you need in the biosimilar.

Now some important points: not every biosimilar is going to be put through the exact same set of tests—like I said, it’s a totality of evidence. So the preclinical testing—for example to establish the amino acid sequence, the post-translational modifications of the drug, the charge of the drug, its pharmacokinetics in patients—need to be roughly the same from drug to drug. But it may be 40 to 100 numbers of tests that really make it seem like this is kind of the same drug. And after all of that preclinical testing is done, the clinical trials are done in far fewer patients and in fewer indications. So whereas Remicade may have been tested in six different…, seven different disease states, when put to a biosimilar evaluation, infliximab (a biosimilar of Remicade) might only be tested in ankylosing spondylitis, in rheumatoid arthritis …not in psoriasis. And the FDA would say, good enough: the data are clean enough, comparable enough that in RA and ankylosing spondylitis we can now extrapolate to psoriasis or other disease states for which infliximab (Remicade) is approved. So you have to be comfortable with that. In some instances (for example with adalimumab) we're going to get clinical trials in psoriasis and the converse is true: practitioners who do treatments for rheumatoid arthritis will have to accept the psoriasis data and not know data in rheumatoid arthritis. So that's called extrapolation; and therefore the company that's trying to get approval for a biosimilar has a lower standard with regard to number of indications tested and within those clinical trials the number of patients tested is far fewer, because they're not going to go up against the placebo group. You’re not going to see placebo arms in these clinical trials. You really just see head-to-head matchups between the biosimilar and its reference—it's head-to-head.

Now what happens in these head-to-head matchups is they go to the clinical trials primary endpoint that was originally used for the reference in that disease state, and then they thereafter may switch some patients from the reference to the biosimilar and some from the biosimilar to the reference; and other patients they just keep on the reference or the biosimilar. So they have multiple comparators over time and they make sure that the switch does not lead to increased safety issues or concerns …and the switch does not lead to immunogenicity …and the switch does not lead correlatively to a loss of efficacy. You basically want the switch to be an inert concept, it has no effect. Because that may occur long run: we may have interchangeability and switching at the pharmacy level unbeknownst to you. It depends on where you live in the regulatory environment in which you are prescribing drugs. It might be the case that a pharmacist can’t switch drug without your permission, but in some states and locales the switch may occur without your knowledge and you at least need to know from clinical studies that the switch is inert.

And now what I can tell you is the sum total of all studies that I've seen to date for not only infliximab (Remicade)—adalimumab (Humira), etanercept (Enbrel)—have shown very professionally done clinical trials that demonstrate the biosimilar performs as it should comparably to the reference product. In other words the margins of variability between the two drugs in the right patient populations are very small and actually within the goal posts that were set a priori prior to the study ever being commenced. Additionally there are no safety signals that are distinguishing the biosimilars. There are no differences in pharmacokinetics; they’re completely overlapping curves. There are no differences in immunogenicity, so that switching doesn't appear to be relevant on any level: immunogenicity, safety, ethics. And therefore what I can tell you is that while biosimilars may have to go through a less rigorous process for approval at all levels, the process is still adequately rigorous, very professionally conducted. The data that are generated over years of study of these biosimilars are quite high caliber. And in sum total the decisions being reached by the regulatory authorities to approve the biosimilars—which has already occurred to date with regard to Remicade’s biosimilar infliximab and Humira (adalimumab) and Enbrel (etanercept)—the approvals are reasonable.

I think what’s left to be seen for the most part will be: do we have in place post-marketing surveillance packages that allow us to detect rare safety issues that are gravitating towards one biosimilar in particular and not others? So that we really know if there were a rare issue of safety or immunogenicity or loss of efficacy, that it's due to one manufacturer and one drug. Because there will be many of these drugs; there won’t just be one biosimilar. There may be six to ten made by six to ten different companies all trying to emulate the success of the reference product and we will need to have post-marketing surveillance that's rigorous to really detect these rare issues. The other issue will be: are they going to be named in a way that we really know what’s happening when a patient is switched? Can we know which drug the patient’s getting by the name the patient’s drug has on the label? And finally a big issue in my mind, as I alluded to earlier: if the pharmacy is allowed to switch patients, because ultimately the payer will mandate the pharmacy switch those patients, will we be notified as practitioners that the switch occurred? Or will it be just happenstance: the patient comes back and tells you the color of their injector device went from red to blue and it's a little bit different now. That would be a little unnerving to me. I would hope that I can control the switching process to some extent or at least be notified immediately if the switch does occur. Now putting all those issues aside and to conclude, I think it's important to consider that biosimilars ultimately may lower costs. I think it's kind of logical to think (at least in many locales around the world) cost reduction will occur, and because cost reduction occurs access will increase. The degree of those effects is left to be seen: is it going to be 10% or 30% or 50% on those issues? No one really knows. In 10 years we will be able to study the issue and really give you a better concept. But I think it’s important to know the background behind approval and what goes into approval and at least be well educated so that we don’t have panic with regard to the concept of biosimilars; in fact, we have a degree of comfort. Thank you very much.

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