IBD Drive Time: Christina Ha, MD, on Biosimilars

Guest Christina Ha, MD, from the Mayo Clinic in Arizona, reviews key points about biosimilar therapies, including reassuring patients and countering the "nocebo" effect, with hosts Drs Raymond Cross and Millie Long.

Raymond Cross, MD, is a professor of medicine and director of the IBD Program at the University of Maryland School of Medicine in Baltimore. Millie Long, MD, is a professor of medicine, vice chief of education and director of the fellowship program in the Division of Gastroenterology and Hepatology at the University of North Carolina at Chapel Hill. Christina Ha, MD, is a gastroenterologist specializing in the care of patients with inflammatory bowel diseases at the Mayo Clinic in Scottsdale, Arizona.

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TRANSCRIPT:

Any views and opinions expressed or those of the authors and or participants do not necessarily reflect the views, policy, or position of the Gastroenterology Learning Network or HMP Global, their employees and affiliates.

Millie Long:

Hi, this is Millie Long from University of North Carolina, one of the co-hosts of IBD Drive Time. And with me today I have Ray Cross, University of Maryland Drive Time co-host, and our guest for today is Christina Ha, who is from Mayo, Arizona, and she's going to be speaking to us today about biosimilars. And this is something that if it hasn't hit your practice yet, will certainly hit your practice with some of the newer adalimumab biosimilars. And so we have a lot of questions and over the next 20 minutes we're going to dig into biosimilars and IBD. So welcome Tina.

Christina Ha:

Thanks for having me.

Millie Long:

So again, this podcast is sponsored by the Gastroenterology Learning Network and Advances in IBD, and we're excited to talk about a topic that really we're starting to have more and more data on, but for some of our patients, they're hearing about this for the first time. So we really want to be able to explain a little bit about biosimilars. So Tina, it is kind of a good time to review some terminology which I think can be confusing for providers and patients alike. So just starting with some definitions, what is a biosimilar?

Christina Ha:

That's a great question and I'm glad we're talking about this because you know what I think, is in a few years the topic of biosimilars will just sort of be a moot point because biosimilars represent a type of medication, it's not a brand new class of medications, but they're just additional options of let's say anti-TNFs or in the very near future interleukins. So what a biosimilar is, it's something that I like to say is clinically equivalent to the reference or the originator product. So for what it's worth, it's the brand name product. They can't be structurally equivalent because these are large protein-based compounds and there's so much batch to batch variation even within the original or reference product that you'll never have an exempt covering copy.

But the FDA mandates that the biosimilars undergo rigorous studies with various levels of data collection in order to demonstrate clinical equivalence. So it's not superior, it's not inferior, but in clinical practice you can utilize it in the exact same way and expect the exact same outcome as well as safety events.

Millie Long:

Great. And a couple of other definitions just to get out there before we dig into more of the data. What does indication extrapolation mean? I've seen this on some of the studies.

Christina Ha:

Yeah. So indication extrapolation, for example, for infliximab, infliximab is FDA approved for multiple disease states, so ulcerative colitis, rheumatoid arthritis, Crohn's disease, et cetera. So indication extrapolation in the setting of biosimilars means that if they've shown clinical equivalence in one FDA approved disease state such as rheumatoid arthritis, then you can extrapolate that data to presume it's going to be clinically equivalent for all the other FDA disease states. And the reason why that's important is it's not cost-effective or pragmatic to do head-to-head randomized controlled trials for the biosimilar for every single disease state if it's already gone through that process through the FDA for something that's clinically equivalent.

Millie Long:

Okay, great. But I can see how that could potentially cause some concerns for some of our patients if they see that it was studied in a different disease population.

Christina Ha:

Oh, absolutely. And even though the FDA allows for indication extrapolation, what's really important is to be familiar with some of the pivotal studies that are present in ulcerative colitis and Crohn's disease for these biosimilars. And they do exist and there's ample data that show that the results are nearly identical, which is pretty uncommon when you're doing any kind of a head-to-head study to see the same response rates, remission rates, drug levels, as well as adverse events between product A and product B.

Millie Long:

Great. So one last question, and this is hitting the news recently because there is one new adalimumab biosimilar that has actually met this indication, but what does interchangeability mean?

Christina Ha:

Yeah, so interchangeability is really an important concept for us to understand. So right now there is one FDA approved biosimilar for adalimumab and I'm going to use a trained name here, it's called Cyltezo, C-Y-L-T-E-Z-O. That was granted FDA approval for interchangeability. Now there's different levels of "interchangeability". When you break it down, what we are most familiar with biosimilars right now is something that's called transition or switching, which means if you've been on the reference product or the brand name product and you've been on a stable dose, then you switch over to the biosimilar and you expect the same outcome, that is interchangeability in the sense of you've made a medical decision to just transition from one agent to another. But interchangeability from the FDA approval state means that you don't expect any difference going from product A to product B, back to product A, back to product B, you expect the exact same outcome in terms of effectiveness as well as adverse events.

That does require a clinical study. And so in the case of adalimumab, that was demonstrated in what's called the VOLTAIRE study for plaque psoriasis because they actually had multiple switches from reference to biosimilar and back and there were no differences in clinical outcomes as well as drug concentrations. So that's why that has interchangeability, which allows for automatic substitution at the pharmacy level and that is what could potentially impact our patients because we don't know exactly how that automatic substitution based on interchangeability will play out in clinical practice in terms of how long we'll know and how quickly we can get approvals.

Millie Long:

So it certainly seems like from the patient perspective, and I actually probably need to start doing this in my practice, is to mention to them that this is coming and they shouldn't worry about it potentially because it may be that we don't as providers get notified when this is switched and it'll likely look a little different too. Right?

Christina Ha:

Yeah, absolutely. And especially for adalimumab because the mode of delivery may look a little bit different. For infliximab, switching from one agent to the other, it's really hard to tell the difference because getting an infusion, but the packaging and the mode of delivery will be different across the nine now FDA approved biosimilars and many of them based on the insurance company may have contracts to be at a lower tier for coverage. So the biosimilars may be preferred.

So I think what's really important is to have a baseline familiarity of what biosimilars are and to use, not the brand names when you're prescribing medications, but what they are. So in my practice I say, "We are starting adalimumab," or, "You're going to continue adalimumab." And for some patients I'll start to say, "There are FDA approved biosimilars to adalimumab, but they are clinically equivalent," to try to prepare them and explain the data because we do have to prepare our patients because when there is a visual difference, the possibility of something called the nocebo effect where patients perceive that they're going to have a worse result may be higher. And that's important just to expand a little bit more, is that if somebody is used to getting, for example, a high concentration self-injectable pen, but their insurance tells them moving forward, "Now you're going to be receiving a low concentration, a citrate free syringe," the mode of delivery is different. And so we have to prepare our patients for that potential worry about not having the same outcome.

Millie Long:

Absolutely. Education is key. And I remember in my practice how important it was when the infliximab biosimilars became more prevalent is really having the same consistent message from the nurse who infused them to me, to everyone that this really the data or that this should have the same response. So I think that kind of getting prepared for this because it's coming likely this year in our practices as... I mean the drugs are obviously FDA approved, but I think we'll start seeing them in our practices later this year.

Christina Ha:

Yeah. And actually already in contracts, for example in our area, United has three FDA approved adalimumab biosimilars as tier two, whereas the reference product is tier five. And so we just have to really show confidence in the data and the evidence just like we'd show confidence in any new mechanism of action knowing that this isn't, but also the consequences of delays and delays in treatment actually are what's... are going to be associated with the worst outcomes for people who are doing well.

Millie Long:

Absolutely. So one last question before I pass things over to Dr. Cross for his questions. We've talked a little bit briefly about the data that it's reassuring. Are there a few pivotal studies that you want to call out that our listeners should probably really be aware of that would be helpful for them in terms of counseling their patients?

Christina Ha:

Well for infliximab, many of us have a lot more familiarity with infliximab biosimilars just because they've been out for so long. But the main two studies that led to the FDA approval are two studies that are called the PLANETRA, RA stands for rheumatoid arthritis and the PLANETAS, AS stands for ankylosing spondylitis. And those were the two pivotal studies that led to the FDA approval of the first infliximab biosimilar. Now if we're saying we want to know across disease states, there's an important study that was called the NOR-SWITCH study where they actually had two different types of switches. So for patients who were in a stable maintenance dosing of reference infliximab, they randomized into two groups. One group continued with reference infliximab, the other switched, and they explored patients who had all the disease states that had FDA as well as EMA in Europe approval.

But then at week 52, everybody switched from the reference product to the biosimilars. And overall they showed no differences. And I think the fact that there's no differences and especially when they looked at the infliximab levels, they were consistent. That's very important. I mentioned the VOLTAIRE study for plaque psoriasis, which was pivotal to get to the interchangeability status, but there's also something called the VOLTAIRE Crohn's disease study that was published last year and that was primarily led by a colleague Steve Hanauer. And that also showed that there was no differences in terms of week four as well as week 48 outcomes for patients who were treated initially with the reference product or the biosimilar. And that also did include a switch with no differences. So there's a lot of reassuring data.

Millie Long:

Yeah, I think the VOLTAIRE Crohn's data just speak volumes in our disease state. We're seeing very comparable outcomes. Switching is okay. So I think we just need to call it out for what it is, reassure our patients and be comfortable with this switching process.

Christina Ha:

And in the VOLATIRE-CD study, one thing that I would encourage people to look at is look at the graph of the time points from week zero to week 48. They are nearly superimposed. And I think that that's offers so much reassurance and a visual representation of the data that at every single time point, the endpoints were essentially the same.

Millie Long:

Great. Great. Okay. So just a quick reminder as I pass things off to Ray for the next series of questions that we do have an upcoming Advances in IBD Regional Virtual Meeting, which are free to join. We'd love to have you, this takes place on August 17th and 18th, a Thursday and a Friday. You'll see great talks and interactive discussion virtually. So please check out the AIBD Regionals website and sign up today. So let me pass things off to Ray.

Ray Cross:

Thanks Millie. And Tina, you brought up Steve Hanauer and this is actually the second time we've talked about biosimilars on IBD Drive Time, but when Steve did the first episode, we did not have adalimumab biosimilars. So Millie and I thought it was important to revisit this. So I had a question from a referring provider the other day that was timely for this recording. He asked me how he should monitor a patient when he's switching them from the reference product to biosimilar specifically with therapeutic drug monitoring. How do you that in your patients?

Christina Ha:

So I think that it's going to be very... it's going to vary case by case. I don't routinely check therapeutic drug monitoring for a patient who's been on a stable dose, stable regimen who's been in a stable remission and we're just transitioning from one dose to another. I don't, unless the patient has a lot of angst or worry about it despite our extensive counseling. And what Millie said earlier is absolutely correct. We make sure all the key stakeholders are providing the same message. So for the patient who's worried, then I'll check the TDM because you may be surprised, it may be they may have antibodies, their calprotectin may be a little bit elevated, in which case it may not be the right thing to switch to the biosimilar. They may need a little bit more evaluation. But if they have good levels and they continue to be in remission, then we check it again maybe a two or three infusions later. And I've rarely seen a difference for patients who are doing well, but I don't routinely do it.

Ray Cross:

And importantly for the listeners, the levels that we use, so infliximab levels, adalimumab levels, antibodies to those agents are exactly the same with our assays. So there's not a specific assay for an adalimumab biosimilar, they're all the same. And our treat to target and all our strategies we're doing are identical with the biosimilar SDR to the reference. So I think that's important for the listeners. So you mentioned nocebo effect and you explained that really well. Can you give the listeners like a little script, like a 30 to 45 second script on how you explain a transition to your patients in an office setting or even over the phone or maybe through Epic messaging?

Christina Ha:

So we have a consistent script that we use that kind of highlights the data, but we use the key terms that we think will make the highest impact for the patient. And we say there's ample data both in Crohn's disease, ulcerative colitis, as well as all the approved disease states that show they're clinically equivalent. And then we emphasize what you just mentioned, this does not impact the quality of your care. The monitoring strategy is the same, the dosing is the same. The administration for the most part in terms of injectables versus infusions is the same. It doesn't change your plan of care. And what's really important is that we avoid delays because delays, particularly for most patients who've had sort of a rollercoaster or a rocky ride to get into a stable place is much more important to keep them in remission or in response than to risk potentially losing response to stay on a name brand.

And I also have in my files the pictures of the data both for infliximab and adalimumab. And it's pretty powerful. Patients resonate to the relationship you've built with them over time because rarely are we seeing patients once and if they have trust in the conversations and the journey you've had with them, they're much more likely to buy in. And this is true with our teams as well. If they trust your team and they know and they believe that you have their best interests at heart, I rarely have found patients who wouldn't go on with a biosimilar and those who have concerns about it, we spend a little bit more time either with our APPs or nurses to figure out what's the issue. And then usually, they'll be willing to do a few doses of biosimilars and let's say, "Let's check your biomarkers again," and when they realize, "Oh, I feel exactly the same," then they have that much more reassurance.

Ray Cross:

And I presume that if a patient switches and they have a change in symptoms, you're working them up exactly the way you would work up someone who's under reference product.

Christina Ha:

Mm-hmm. And we tell that to the patients too. And for the patients who are a little bit nervous, I'll see them back in the office either with myself or my APP about two to three doses later just to cross T's dot I's so that they know we close that loop to make sure they are reassured.

Ray Cross:

And we all steal from one another. So I've stole from you about the issue about delays and initiating therapy or delays in trying to battle to get the reference approved and I've incorporated that into my counseling. The other thing that I like to use, and this was primarily with infliximab, but now with adalimumab we can say the same thing is with infliximab, there's been over 30 post-marketing changes that have required approval by the FDA. So 1998 infliximab is not the same.

Millie Long:

It's very different. Yeah.

Ray Cross:

In fact from batch to batch, it's not exactly the same. And I thought maybe that would be unsettling for patients, but I think it really helps calm them to understand that you can't make an identical copy and it's just not possible.

Christina Ha:

And I also reassure that biosimilars are not unique to IBD. They've been used for oncology and hematology for a long time and they will be present for every single biologic agent, much like generics. And it's important not to use those terms interchangeably are going to be available for the vast majority of oral agents. So it's just an additional word that we have to include in our nomenclature.

Ray Cross:

So Tina, you did a really nice job breaking down some of the unique challenges with the adalimumab biosimilars related to the delivery devices and how they'll be different from one drug to the other drug. Any other unique challenges with adalimumab biosimilars?

Christina Ha:

Well, I think it's a matter of the timing to ensure that patients are getting their medications on time. And because for example, with infliximab you have weeks in between to coordinate the authorizations and the approvals. But depending on the dose and the interval, you may only have a few days because adalimumab is traditionally given every two weeks or in some cases weekly. So we'll have to see how much advanced notice is given. Usually it'll be, "This is your final prescription and then moving forward you have to switch over to the biosimilars." And the good news about at least the current FDA interchangeable biosimilar is that now actually as of May of 2023, it is also available as a prefilled self-injectable pen.

Millie Long:

Oh, good.

Christina Ha:

So you have both the syringe and the pen form. There will be... it's already in the process of getting FDA approval, another interchangeable biosimilar. Both of these also are citrate free. And that's going to be important because the presence of the citric acid will only amplify the nocebo effect. So I think it's providing the education, as soon as you recognize that the healthcare plans are going to switch over to the biosimilars and make sure you sign them up for the patient savings programs as well as the training. Because when I checked on those sites, they do have the nursing assistance, they have the copay assistance, they have Medicare assistance as well as uninsured assistance. And the copays should not be any more than the reference product. So that also offers reassurance because sometimes one of the concerns is there's so much support for the reference product, are you going to have a similar amount for the biosimilars? And right now, there does appear to be the same.

Ray Cross:

And I think we had some angst about samples. For those of us that can utilize samples, are they going to provide the samples?

Christina Ha:

Yes.

Ray Cross:

And so far, knock on wood, it seems as if that's been the case, that they are providing samples so that we can dose adjust while we appeal and not have to have a delay.

Christina Ha:

And another area just to add in is that sometimes getting some of these self-injectable products is a little bit more of a challenge for our Medicare aged population because oftentimes that has to go through Part D. The benefit with the biosimilars is hopefully now it drops it to a lower tier so that the out-of-pocket cost is less. And then more of the companies, because the pricing is lower, may actually include them in the advantage plans, which are more likely to have prescription coverage of the self injectables.

Ray Cross:

Okay.

Christina Ha:

So that may increase access.

Ray Cross:

Last two questions. Any patient that you wouldn't switch with infliximab or adalimumab?

Christina Ha:

No, the honest truth is there's very few only because it almost always results in delays. The few times I'm able to get an exception is if I'm just starting somebody out and you don't want to muddy the picture because you just want to continue their induction dosing or we just changed their doses or interval. Just let me have two infusions to make sure that we're going to keep them on infliximab, let me get them through induction to make sure we're going to continue adalimumab. Because using that same treat to target principle, you only want to continue a medication if it's working. And so sometimes I'll use that as the argument if they just started, because then it muddies the picture when you're changing too many variables at once. They're coming off prednisone, we're assessing disease activity. But really for any other circumstance, we now have so much more data than we did even two, three years ago that I'm far more comfortable making switches anytime to avoid delays.

Ray Cross:

Yeah, I think it used to be for me, pregnancy and if you're having a big life event that's coming up, trying to delay a little bit. Pregnancy now is not for me a contraindication to switch. But if someone says, "This is my one month trip to Italy, it's a dream trip, this is my bucket list," I'll try to help them until they get back so that they can decrease anxiety. But I agree. I think you can switch everyone. And lastly, one fun question. Tell us something about yourself that we may not know.

Christina Ha:

Oh, well I am currently trying to survive my second year summering in Arizona. So I'm learning to live with all the wildlife that's there, but it's a lot of fun. I'm glad to be in the southwest and we're learning to survive. I have my first adult home with an attached garage, so now I don't have to schlep groceries from a parking lot miles away to my house.

Ray Cross:

You don't have to do it in 110 degrees.

Christina Ha:

I know I will. I'm a real adult now in 110 degree weather.

Ray Cross:

All right Tina, this has been absolutely awesome. Thanks for doing this and we hope to have you back soon.

Christina Ha:

Thank you so much. It's been a lot of fun.

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