Should it, in the absence of any clinical difference, simply be a price issue with you guys?

When you think of the factors that go into the rationale for developing biosimilars, it was to decrease cost.

I didn’t mean that to be a pejorative. I meant that to be an advantage.

No, no, it’s not. It’s not at all. And when you think of the factors that go into a physician’s choice of what therapeutic to use, it’s efficacy, safety, adherence, tolerability, individual patient characteristics, and cost. And, by definition, a biosimilar can’t compete on efficacy. It can’t compete on safety. It can’t compete on tolerability. It can’t compete on adherence (because it’s the same schedule of administration). It’s not going to differ from patient to patient in terms of who you can and can’t use it in. So, you’re left with the cost. It does become a financial factor in defining what it is we use and when we use it.

If you get something that works just as well and it’s less expensive, where’s the problem here? There’s no problem.

There’s no problem unless there is a switch and the patient doesn’t respond to the switch medication as well as they did to the original medication.

Or that the price savings doesn’t get translated to the patient at all.

Let’s address this. Yes, maybe the co-pay is the same, but this is what Gary was talking about. If the entire system saves money so that more people get effective treatment for the same cost, doesn’t that benefit everybody?

Yes, it absolutely does. I think the topics that we’re talking about here, especially when you start looking into the ambulatory space, deal with what these products are costing. And the underlying term, here, is the word rebates. And so now we have pharmaceutical manufacturers who are offering monetary discounts to a pharmacy benefit manager who is then sharing those savings with the payer. These discounts, or these rebates, can often affect the pricing of the drug significantly up to 50% of the cost.

And again, to some degree, they are being driven by the fact that there are less expensive products that are biosimilars.

In terms of the formulary, are biosimilars going to be compared with and placed on the same tier, if you will, as the original drugs?

No. I think that to the extent that now we see managed care companies tiering TNFs (tumor necrosis factors), for example, I think we’re going to see the same tiering based on the biosimilars within that class. So, if previously I had to use Remicade before I could use etanercept, now I’m going to have to use Inflectra before I can use the biosimilar, etanercept, for the same reason.

But that also might change at not even every year but every 6 months, depending on what’s being tiered.

What contract? We’re not privy to any of those pieces of information.

What we’re getting then, I hear, is that under the radar is the flip-flopping of biosimilars because they’ve been shown to be similar. But there may be price differences. And so, people are going to get switched, at least in part, based on price.

And we’ll never have a biosimilar versus biosimilar comparison, clinically, to look at.

Because it’s not set up that way, right?

Gary used the euphemism “nonmedical switching.” That euphemism is used to refer to the case when you’re switching a patient for reasons other than clinical efficacy and, predominantly, because of price.

Well, if you’re doing that, is it necessarily bad, Mr Plan Administrator? Is it really bad to do a nonmedical switch if the evidence suggests that there’s no medical difference?

Just as the biosimilars are unique, your process through P&T (pharmacy and therapeutics) is going to be completely unique for these agents. What does the clinical evidence say? We always start there. Do the product qualities even match our needs? There are certain originator products that come out in vials, but maybe the biologic comes out in syringes. Are we going to have to use more syringes that then negate the cost savings that we had? There are just multiple factors that play into the use, and it’s difficult to say, “Is one agent going to be preferred over another?” You almost have to look at each individually and make that assessment.

If the biosimilars are cheaper, and we would like everybody to be on this class of drugs but we couldn’t put everybody on them because they were very expensive, and now the price is coming down, does the introduction of biosimilars mean that patients, many patients, are going to get put on the best drugs earlier?

This is terrible. Everybody says, “We don’t really know.”

Peter, we don’t really know because we haven’t yet seen the reduction in cost in the United States leading to an increase in access. I don’t think, as Vibeke commented earlier, that it’s going to change our algorithms and guidelines for how we do things. And it’s not going to change the prior authorization requirements for getting a drug to a patient.

We wish it would, but we don’t really know.

In answer to my question, you’ve got a wish list, and that’s one of the wishes?

Right. In the UK, it did as was referred to. This is with something that is a different structure as to payment and approval. If we follow that, then perhaps it will. And that’s part of the hope.

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Cost and Prescribing Considerations for Biosimilars

Let’s take a look now from the rheumatology perspective. How does the approval of biosimilars (in your world) affect the treatment paradigm for rheumatoid disease?

Well, I don’t think it really has. I think in the US it really won’t, because we’ve been fairly aggressive with early diagnosis, early treatment, and successful treatment. I think that we’ve seen, though, that in Eastern Europe and in other areas where biologic therapies have not had much access, it’s made a huge difference. Thus, now, patients are able to get access to these therapies, which are more effective than our synthetics, by and large.

What I hear, though, is that (a) the biosimilars start off a little less expensive, but (b) the threat of the biosimilars is causing a drop across the market in the cost of these agents. In my own tutored way—not being a rheumatologist or a gastrointestinal (GI) specialist&mdash;it would seem to me that if there’s an expensive therapy that’s getting cheaper, it’s going to make it more likely that people are going to get on these drugs, no?

Well, yes and no. I’m not expecting that the insurance plan that’s giving me a hard time now to put a patient on a bio-originator is going to welcome me with open arms because I want to put them on a biosimilar. I think that the same prior authorization requirements and the same hurdles, if you will, are going to be in place for these molecules as they were for the bio-originator. I think we are going to see insurance companies selecting favorite agents based on factors unrelated to their clinical applicability.

One of the big expenses, both in time and money, is all these prior authorizations that we have to fill out (in terms of rheumatology practice).

I think, always, we want to make sure that the patient is at the center of what we’re doing, and you can’t really forget the patient in this. Although with the brand biologics (many of them upwards of multiple thousands of dollars), even with the discounts that we’re seeing now, that cost is still going to translate over to the patient. And that financial toxicity that they have can be just as bad as any side effect that they’re seeing, as well.

If I were a federal government employee, I would think this may not be as good as it sounds. If we open access to more people, we pay more for the government to get more patients taken care of in a more costly way for the entire government. Although you get a cost savings, if you get increased access, that may be a bigger cost to the federal government. So, think of that.

You’re saying that it’s cheaper per patient. But then more patients come in, and the total bill goes up.

But if more people are getting better, is that worth spending?

Yes, of course. That’s why we do what we do.

Is it? I didn’t get a hard “yes” over there. Is that fair?

I’ve done this before. Let’s put this on the table. I could give you a drug which costs 1 cent and does nothing. Nobody would want to prescribe that. I could give you a drug which is equal to the gross national product of the United States and is curative for a previously incurable disease. Nobody can prescribe that. So, there’s this gray scale, which is what you’re talking about. Where does fair come in?

When you do a Markov model, you look at someone and the quality-adjusted life years (QALY) number. It’s something such as, for example, 25,000, that might be a number. And those are the numbers that are bantered about based upon the actual Markov model design.

Well, it varies with the individual end point that you’re looking at. If it’s death, it’s much more valuable. You’re saving someone from dying, as opposed to quality.

But what we’re seeing in the European modeling is that they’re bringing their QALYs down in order to save money for the entire system, and it’s something that has to be done. But we’re leaving a dimension out, Peter, and that is, does the patient benefit? The cost of the therapy may be cheaper to the provider. It may be cheaper to the payer but not to the patient.

What do you mean by that? If it’s cheaper to the system and the patient is getting a good drug, where is the patient losing? What are you implying?

Well, if the patient has a $500 co-pay for the bio-originator, it’s not clear that their co-pay will change merely because there’s been a discount that’s been related to the managed care company.

I think it’s also yet to be seen, too, as to what the manufacturer response will be to assist patients. Right now, many branded products of biologics have co-pay assistance and means through manufacturer assistance to help reduce this financial burden. But the same hasn’t been seen with biosimilars yet. And also, when you consider the generic (if that’s kind of what we’re comparing it to—the previous branded generic products), there isn’t a lot of assistance out there for generic-type products. Will that trend follow as we look into more biosimilars?

Let’s take a look in the GI sphere, Gary. In the absence of what can be termed “head-to-head clinical data,” how do you use this extrapolated data in your area for the infliximab biosimilars, and how do you evaluate the risk and the benefit of these drugs?

I think, again, you have to look in several ways. Those that are on the originating product feel comfortable that this is the initial product. Those that have had a prior trial with an anti-TNF (anti-tumor necrosis factor) and are not currently on it feel comfortable, perhaps, trying (although we don’t have large, adequately powered studies to look at that). It’s the nonmedical switch and the multiple switches that are the big concerns for the patients and for the providers. So, I think we need better data, if you would, with adequately powered studies.

There was a recent study at the European meetings that looked at 680 patients with inflammatory bowel disease (IBD), particularly. They said that no further signal differences were seen at the end of the trial. So, this is a larger study, if you would, focusing just on IBD because many of the studies have been on other disease states, if you would.

What I keep hearing—the drumbeat that I hear across this panel&mdash;is that biosimilars are, in fact, similar, right? And there’s no signal here. We’d like more data, but the data we have is really good.

Use of Biosimilars in Inflammatory Diseases

Let’s go on with this discussion and talk about evidence, because everybody wants evidence. We like evidence. Evidence is good. Why don’t you start us off by telling us what your clinical experience has been, Gary, with biosimilars? How comfortable are you prescribing the biosimilars?

It might be better to ask someone else, Peter, because in our health system, as of yet, we haven’t had the opportunity. There’s been a cost differential, and it’s actually higher to use a biosimilar than the originator.

I’m sorry, can we just stop for a moment? It’s more expensive to use the biosimilar where you come from?

We’re an educational health system that has a large indigent population, so we get deep discounts with the use of medications and in pricing. Perhaps others would like to comment on this more from an economic standpoint? I’m not an economically focused individual when it comes to the clinical practice. It’s more based on our health system’s deals, if you would, that they’ve made with various corporations.

At the end of the day, what we’ve heard is that biosimilars were authorized to decrease the cost of drugs and, in doing so, increase access. Now, decreasing cost is related to how well the biosimilar manufacturer can negotiate versus how well the bio-originator manufacturer can negotiate. You can anticipate that you’re not going to see the bio-originator manufacturer stand still while someone else comes in and tries to eat their lunch. So, I’m not surprised to hear that there may be systems in which the bio-originator is priced even lower than the biosimilar, which was promised to be the reduced price.

One thing I would add is that there’s a portfolio of products that various corporations may have, and there may be discounts for use of the various products that this particular corporation has. And that’s, perhaps, what’s operating.

And we have no way of knowing what those discounts are. But if there is competition, then we can see what might happen based on what happened, for instance, in Norway, where the biosimilar Inflectra was deeply discounted to a 69% discount off the price. And that was because there was a competition every year around the price.

But that’s a single tender. A single system with a single tender.

That’s a single tender system. We don’t have that here. And since we have pharmacy benefit managers who decide and, also, this discounting with portfolios that we’re not aware of, it’s very hard for us to know what’s going to be cheaper or by how much.

Let me back this up, because the import of my question—at first, at least&mdash;was clinically. You’re all using these biosimilars clinically. Have you tried them?

Most of them are tied up in the court system, so we can’t even try them.

We’ve only recently had the first one approved at our institution, so our experience with it is limited. But as to the comfort level of using it, I can tell you that I divide patients into 3 categories. For new starts, it’s very difficult to make an argument that you wouldn’t put a patient on a biosimilar, because it is a biosimilar molecule. And then you have patients who are stable, and they achieved their stability of their disease (whatever disease we’re talking about) relatively easily. I would probably not have a great deal of difficulty switching that patient. And then you have the patients that you really struggled with, over a great deal of time, to get to the point of low disease activity and remission. Those are the patients who are referred to as the “sleeping baby.” You don’t want anything done to disturb the sleeping baby. I think I would have more difficulty switching that patient. Indeed, the patient would have more difficulty accepting a switch.

Right. I foresee a patient going, “Whoa, whoa, whoa. We just got this fixed and you want to go fiddling with this?”

Peter, the big issue is not just 1 switch but multiple switches. You have agent X that then is started. Agent Y is given because of a deal that’s made. And then, an originator might be used. And the question is, what effect does that have? Unfortunately, we don’t have data to guide us on that.

When we talk about evidence-based care, we need evidence.

Evidence would be nice. In the meantime, what are we talking about in terms of the financial impact? There’s this NOR-SWITCH trial out there. I think you alluded to that. Tell me about that.

The NOR-SWITCH trial was funded by the Norwegian government, and what it did is it looked to examine the effects of switching the originator, infliximab, to the biosimilar product (looking really at safety and efficacy) across 6 different inflammatory diseases. And what they found in that study was that there was noninferiority when comparing these 2 products.

So, there’s definitely some promise when we look to switching products to formulary or considering the use of biosimilars. But I think the thing that’s just as important is what it told us (which is kind of what it didn’t tell us). And that’s really around what we’ve already alluded to here with true practice. This was in a box. Now, we’re talking about what happens with a patient—again, in the acute care setting&mdash;who gets 1 product. They go to the ambulatory setting, and a payer dictates that they get a different biosimilar. So, the switching of real-world possibilities&mdash;it’s hard to extrapolate that data and put it into a US setting.

But we do have the data from the DANBIO registry, where the Danish government mandated that everyone go to the biosimilar. And so, now with that data, as well as with the NOR-SWITCH data, what we can really say is that the time to loss of effect is highly similar and that, basically, patients across these different diseases also have a similar experience. The NOR-SWITCH study was actually a time-to-treatment failure across all these different diseases, and none of them were of sufficient sample size to be looked at individually. You could only really look at the whole group.

With these switch trials, were they using random drugs with different 4-letter suffixes, or was only 1 biosimilar compared?

Only 1. So, that really doesn’t answer your question, which is, “I went here. I got A. I went there, and I got B. They’re all biosimilar. They should work. Where’s the evidence?”

The question that comes up is, should we use a concurrent immune modulator, as is very commonly done in the rheumatoid arthritis (RA) world to lessen immunogenicity? Immunogenicity is one of the biggest issues that we have a concern in in the gastroenterology arena, if you will.

We have it, too, in the RA arena. We actually know that it is a good idea to use background therapy, and there’s a variety of agents that you can use. Low dose is sufficient (which is one of the points), because patients don’t really take background methotrexate once they get on a biologic.

But we don’t make our assessment of whether the drug is working in a given patient based on knowledge of immunogenicity. If the drug is working, it really doesn’t matter to me if they’re formulating antibodies. If the drug is not working, then it really doesn’t matter to me, either. I’m going to switch the drug. So, the rationale for the switch in the rheumatology world is less concerned about that than it is for Gary.

And on a group basis, you can say, “OK, immunogenicity is associated with loss of benefit,” and, therefore, switch. But, on an individual patient basis, that may not be true at all. There are plenty of patients with antidrug antibodies who are still responding.

You’re the ultimate clinician in this regard. “Is this drug working for my patient? If it is, great. If not, let’s do something else.” Fair?

You have to be careful in gastroenterology, because there’s silent disease in Crohn’s, for example. You may feel great, but the disease is progressing. It’s a progressive, destructive disease that leads to fistula, strictures, and abscesses. And, if we think of that, it may be 8 to 10 years that we need to use medications to prevent disease from occurring, surgically. And that’s something that is not the same as, necessarily, other diseases.

Well, we know that’s the case in rheumatology, as well. We know that people who are in numerical remission, by whatever standard we’re using, may still have active synovitis or active erosions going on. Our challenge becomes, how do you match someone who’s feeling good with the fact that their pathology may be advancing?

That’s why the FDA (Food and Drug Administration) has gone with originators to the PRO—the patient reported outcome&mdash;plus mucosal assessment in the IBD (inflammatory bowel disease) world. Mucosal assessment is, arguably, the most important aspect of what we do.

And, again, if they’ve done it with the original drug, they feel the biosimilar is similar enough that they should repeat all of that. So, what does that do from managed care’s perspective? Are the European studies translatable to the United States? And if so, how and what is that going to do to the formularies?

I think yes and no. The data is promising but, again, it’s limited in that space and in that box. It’s hard to apply it to some of the standards that we have in care in the US, so I think a lot of it is yet to be seen.

Do you see formulary managers saying, “Look at this. There’s a cost savings here. It’s a biosimilar, and the European studies look great. Let’s take the original drug off.” Do you see that?

No. Again, you’re talking about the waking of the sleeping baby. You have a number of patients. A lot of times, it’s about consumer choice. It’s about provider choice. We have a number of patients who are being successfully treated on a particular therapy. I think it’s unfair for us to necessarily take them away and maybe limit the success of care that they’re having. I think there’s an equal playing field for both, and there might be preferred options (just like there are in any other payer networks). But I don’t know if we can necessarily pick one and limit choice.

I heard a word, “unfair,” from a payer. You know that that’s often the case with other disease states with other drugs. Eventually, when things get settled out, and some therapies are shown to be effective and equivalent, they go into lower cost. That’s what’s in the formulary, and then the clinicians go to war. That’s a fair statement, isn’t it?

So, we’re going to have to see how that plays out.

Clinical Experience With Biosimilars

What I really want to do now is make this little pivot. The original drug and, presumably, the biosimilar were approved for use in specific disease states, but we know that you guys, for example, are using some biologic drugs on diseases for which the original drug was not necessarily designed or intended. So, what about using the biosimilars for those same applications?

If the molecule is very similar, then the regulatory agency and the US FDA have allowed interchangeability, if you would, for the specific areas that were approved initially for the originator. That’s something that has to go through a process. For example, the initial FDA approval for Remicade was Crohn’s. It’s used for rheumatoid arthritis, as well. These are things that have been interchangeable as a consequence.

Well, let’s be careful. We’re using 2 terms interchangeably.

We were talking about interchangeability. I think what we mean is extrapolation—where the biosimilar, having been approved in 1 indication, is allowed to be used in virtually all other indications that the originator is marketed for. Now, interchangeability is a very different concept entirely.

Right. The extrapolation has been interesting because, by and large, the trials that have been done, maybe 1 or possibly 2 clinical trials, [were] usually done in diseases where we have really well-performing outcome measures, and they can best differentiate and have best differentiated active-from-placebo with the reference products.

So, the majority of the trials, at least with the TNF [tumor necrosis factor] inhibitors, have been in either psoriasis or rheumatoid arthritis. In part, that’s because the Crohn’s disease and ulcerative colitis end points are not as “well behaved.” So, the extrapolation is from a relatively different set of diseases to ones where there may be a little bit more variability because of the protein-losing enteropathy. But we’ve actually understood that the mechanism of action across all these diseases is highly similar. And thus, if you can prove efficacy and highly similar behavior, clinically, in one, you should be able to extrapolate to the others. I think one of the concerns is that the FDA has made it very clear that the label for a biosimilar is identical to the label for the reference product (with the exception of the strange name, which is a formal name with a randomly generated 4-letter suffix). That’s going to make it very hard for people to try to figure out how to report pharmacovigilance.

Why would they make it hard if what they’re doing is they’re adding? Let’s be very clear. What is this little 4-letter doodah that comes at the end of a biosimilar, which wasn’t at the end of the original?

I’ll go through that for you, Peter. So, for example, Remicade is infliximab-hjmt now. We have Inflectra, which was approved in April 2016, and that’s infliximab-dyyb. Then we have Renflexis, approved April 2017, which is infliximab-abda. And then, Amjevita, in September 2016, which is atto.

We’re not. Can everybody just look over here? He’s got it written down over there. He’s cheating.

I wrote them down so I could remember. But the issue is, this is for safety.

If there’s a safety issue that comes up with a particular drug, this will be registered that it was administered, and then one can go back to that group. Say, for example, there is some untoward event that comes about. You can then see which agent the patient had by going back.

And by looking up that directly. So, that’s the way that it helps tracking of this.

That’s often going to be distal to us, because we’re going to write a prescription for infliximab, and we may not always know what the 4-letter suffix is that the patient is getting.

Or we may not even know which infliximab the patient is going to get.

But that’s not the key. The key is, you need a way to track things, and that’s the important issue if there is a safety signal that comes about. I would a little bit disagree with your take on the Crohn’s and ulcerative colitis. I think, if you look at this from the standpoint of inflammatory bowel disease, they’re more expensive trials, and it’s much easier to measure by taking an x-ray and getting a Sharp score (or whatever is deemed to be appropriate) than it is to do a colonoscopy, endoscopy, etcetera. And they’re much cheaper trials to run. I think that’s been a big factor in what’s done, and I, rather, would guess that we’re not going to see many, if any, done with inflammatory bowel disease.

But, Peter, to your point, when you prescribe aspirin, you don’t know if the patient is getting Bayer or St. Joseph’s or Costco or Walmart. You know that they’re getting aspirin, but you don’t know what brand they’re getting. Similarly, we have a way of tracking which brand of infliximab the patient may be getting from the last 4 letters or the suffix. But, at the time that we’re writing for it, we may not know what’s actually being received.

You don’t have to write for those 4 letters?

If somebody knows somewhere in the pharmacy…

Right. At the point of dispensing or at the point of paying, somebody is recording which of these biosimilars, if not the original drug, was actually administered.

And the variation could be 80% to 120% or so, as a standard within the small molecules. And the same occurs for the biosimilars.

What does that mean—the variability could be 80% to 120%?

If you’re prescribing 40 mg of prednisone, they may get as low as 80% of that to as high as 120%, based on a generic product. That’s the current standard within the FDA.

Right. How does that apply to the biosimilars?

Right. It’s an international standard that is with all products that are manufactured.

I’d be interested in hearing Cole’s experience in tracking the use of a biosimilar agent, now that we have both the originator’s name and the biosimilar’s name.

Sure. I think a lot of it is dependent upon when you look at the continuum of care. Exactly as you stated, you might get a prescribed product, and you’re going to write that biosimilar out there, but you don’t necessarily know what’s going to be dispensed in the hospital (in the acute care setting) versus what’s going to be dispensed in the ambulatory setting. So, there’s that mix of product, and it kind of helps muddy the waters.

We’re going to get into this later, but I want to just ask this right now because this was a big issue several years ago. If you wrote for the trade name drug, the original drug, there was a little checkbox: “Can we administer the generic?” Is that happening here with the biosimilars?

In today’s market. For the products that are out there, there are 28 states right now that allow for interchangeability. But the standard that exists for the generic products (that have been around for a while) is not the same standard that exists for biosimilars. And even the interchangeability access that you have in some states has nuances.

Interchangeability is different. It’s another level of regulatory approval.

Right. But I guess what I’m asking is, if you write for this generic (and I don’t mean the generic drug, I mean the generic name without that little suffix), they can give any of these, and they’re just going to track it back, and they’ll keep taking notes?

Naming of Biosimilars

There are the bioequivalence data from the Biologics Price Competition Innovation Act. Help me here. What on earth is that? Is that a different way of approving biologicals versus biosimilars?

It’s part of the Affordable Care Act, which is very interesting, because if that gets repealed, I don’t know how the FDA will actually be able to regulate biosimilars. But, essentially, what it’s saying is that a biosimilar must be highly similar to the reference product (based on a totality of the evidence). That means the structural characterization and functional characterization—so, physical, chemical, and biologic characterization.

There’s some limited preclinical data, usually based on what was done with the reference product, and then, finally, the clinical trials. There’s a human PK/PD [pharmacokinetics/pharmacodynamics] study, and then usually 1 or maybe 2 studies, maybe, in 1 or 2 indications to show that, in fact, the product behaves clinically no differently from the reference product.

This is the standard that was used to approve Renflexis and Inflectra?

Right. So, that’s the standard they’re using?

But the point is, it’s an abbreviated pathway. The totality of the evidence says, as Vibeke correctly points out, it relates, lately, to the analytical, the preclinical, and the pharmacokinetics and pharmacodynamics. The clinical experience is really the tip of the iceberg for a biosimilar. For a bio-originator, for each indication, the manufacturer has to conduct 2 replicate trials for each thing they want to market it for. For a biosimilar, that’s not the case.

Again, let’s come back to this difference. Generic drugs have got to be the same drug, right?

Right. But based only on bioequivalence data (only on PK and, if you have it, PD—pharmacodynamics). So, that’s all you have to do, which is probably why we’ve seen, with generic pills, that some of them don’t behave as well as the originator.

And, Peter, one other point to note is that there are differences. Administration in a generic is oral, typically, whereas that as a biologic is often parenteral. Another thing, as well, is the mechanism of action. A small molecule that is a generic, if you would, is going to be an enzyme inhibitor, whereas this is a biologic blocking agent, per se.

You did mention something. I want to circle back. There’s the PK/PD that you mentioned in terms of these drugs. These are biologicals. Is there a formal PK and a formal PD for these drugs? They get in and they go to work. Do they wash out?

For infliximab, it’s linear pharmacokinetics, and it’s well established. In the area of inflammatory bowel disease, we do therapeutic trough monitoring. And a level of 5 to 10 (that trough) is classically associated with remission, whereas a level of 11 (for example) or higher has been shown to correlate with fistula healing, and a level of 10 or higher, mucosal healing, based on the recent data that we’ve elucidated in the gastrointestinal arena, if you would.

My view of these drugs (and clearly it’s wrong, based on what you’re telling me) was that you put these drugs in, and it’s like these little molecules are creeping along and doing stuff and changing stuff. They’re effective when they’re there, and when they go away, they’re not effective.

One of the key things to recognize, as well, is that albumin is one of the best predictors. Serum albumin is the best predictor of response, pharmacokinetically, to a biologic (infliximab).

It’s a reflection of what’s going on in the gastrointestinal world in the bowel. You lose albumin in the bowel when you have active inflammation. And actually, levels of infliximab have been measured in the stool of patients. It’s not a fun job to do, but it’s been measured and recognized that they’re higher in patients who have active disease.

This is as good a time as any to recognize that there are differences in our specialties in what we use and how we use it. Concepts of antidrug antibodies, concepts of trough levels, and concepts of albumin levels are really not used in rheumatology or, as far as I’m aware, in dermatology, either. They seemed to be unique to gastroenterology.

I think they’re not used because we don’t have protein-losing enteropathy in our diseases. We’ve been treating our patients so effectively that they don’t have hypoalbuminemia any longer. So, in fact, a monoclonal or soluble receptor will have the same PK in any of our diseases. It will be different in gastroenterology for the reasons that we talked about, but it will be the same in, for instance, psoriasis.

Now, I also read that you’ve got preclinical studies that these biosimilars are forced to meet. Animal data—it’s got to show at least some animal data, right? Is that fair?

OK. And then there are clinical studies that are post-marketing pharmacovigilance in addition to PK/PD. How do you do that?

No. Although there’s a lot of interest in it, particularly in Europe where it is mandated and we have been able to see a lot of information based on those mandates, in the US, once a biosimilar is approved as a biosimilar, we consider that the post-marketing surveillance from the reference product would be more than sufficient.

Really? OK, so let’s get this very clear. Once they’ve established that a biosimilar is similar, they can turn around and say, “Well, we did that part. And by extension, we can use the post-marketing data on the original drug as monitoring for the similar drug.”

Well, it’s not that they can use it. It’s that the post-marketing requirement for the reference product has already been completed, and thus, there really isn’t a need for further studying. We do want to have people report if there are adverse events that are significant, but it’s not the same thing as having to do a formal type of a registry study.

But to be specific, if there’s no post-marketing requirement on the bio-originator, there will be no post-marketing requirements on the biosimilar. The package insert of the biosimilar will be identical to the package insert for the biosimilar. The only thing that we’re particularly interested in, and we’ll get into this in a few minutes, is, how do we differentiate between the use of a biosimilar and the use of a bio-originator? And that gets to the scheme of some concocted 4-letter suffix that seems to bear no relationship to the manufacturer.

Approval Process for Biosimilars 

What are the physical differences between a biosimilar and a generic?

To start, there are different ways that they’re made. Biosimilars are made in host cell lines, whereas the generics are small molecules.

It’s not “I know where this carbon goes and where this oxygen should be,” it’s “I’m going to grow this, and it should work the same.” Right?

Well, yes and no. I’m sure what will develop in a few minutes is that the primary structure, the sequencing of the amino acids, has to be the same for a biosimilar and for a bio-originator.

It’s the tertiary structure, the afucosylation, and all different variations which may occur. It’s a different chemical overall tertiary structure that makes a difference.

And I think you said that they were grown, not manufactured?

That’s where a lot of the variability can occur. So, during the manufacturing process (when the cells are making the product), we get changes to the secondary, tertiary, and even the quaternary structure. Now, those changes have to be very, very small, so that, in fact, the biosimilar will behave exactly like or highly similar to the reference product. We’ve learned a lot about this because we’ve learned so much about manufacturing biologics over the last 30 years. And thus, we can control for these things. But, more importantly, we can actually test for the variability to assess that any of the variability that occurs doesn’t change how the product actually behaves.

I have this image based on what you said: that when the cells don’t listen to what you tell them, they’re going to do what they want to do.

And the trick is to make the cells do enough to make this behave well. Is that fair?

That’s fair. And the other process is that manufacturing these products has improved so much in the last 20 to 30 years with much better scale at much more efficiency of production. All that technology has now allowed us to reverse engineer these products.

These are biologicals. These are not pills that you put, I hesitate to say, in the medicine cabinet in your bathroom (because you shouldn’t put pills there). They’re different. They’re not as stable, are they?

No, they’re not. They can be or they might not be, depending upon the molecule.

Well, there’s a definitive statement there.

Well, yes. It depends on the molecule that we’re talking about. But the working definition is that there can be differences in the molecule between a biosimilar and a bio-originator (the reference molecule), but they can’t be clinically meaningful. They can’t affect the safety. They can’t affect the efficacy. They can’t affect the purity or the potency of the molecule that we’re dealing with.

So, we’re focusing on end effect, as opposed to absolute mirrored structure.

What are we dealing with in terms of immunogenicity potential?

Essentially, chemical products really have very little, if any, immunogenicity, but all biologics are immunogenic, and they’re different in different people. What’s been interesting about the biosimilar process is that we’ve actually learned a lot more about immunogenicity of both the biosimilar and the reference product because the assays that we’re using now to detect immunogenicity are much more sensitive. They’re much more modern.

Differences Between Biosimilars and Generic Drugs

 titled “Clinician and Managed Care Insights on Biosimilars for Inflammatory Diseases.” Biologic products constitute less than 1% of all prescriptions dispensed in the United States, but they account for more than one-fourth of all US prescription spending. Today’s panel of experts for this 

 is going to provide an overview of biosimilars, clinician and patient understanding of the biologics landscape, and access considerations. We are also going to focus on a discussion of newly approved biosimilars for inflammatory diseases and how they may change the landscape for treating these diseases from a clinical and from a cost perspective.

I am Dr Peter Salgo. I’m a professor of medicine and anesthesiology at Columbia University College of Physicians and Surgeons. I’m associate director of Surgical Intensive Care at New York—Presbyterian Hospital.

Participating with me today on our distinguished panel are Dr Allan Gibofsky, professor of medicine for Healthcare Policy and Research at Weill Medical College of Cornell University and attending rheumatologist at the Hospital for Special Surgery in New York, New York; Dr Gary Lichtenstein, professor of medicine and director of the Inflammatory Bowel Disease Center at the Hospital of the University of Pennsylvania Health System, in Philadelphia, Pennsylvania; Dr Cole Wilson, assistant vice president of Outpatient Pharmacy Services at the Carolinas Health Care System; and Dr Vibeke Strand, biopharmaceutical consultant and adjunct clinical professor [in] the Division of Immunology/Rheumatology at the Stanford University School of Medicine, in Stanford, California. I want to thank all of you for being here today.

Let’s get right to the point: biosimilars; biologics. Why don’t we discuss some of the gaps in knowledge and common misunderstandings here related to biosimilars among medical professionals and patients? First of all, what are biosimilars?

 Biosimilars are biologically active agents that are similar to biologics. They take their name as derived from that concept. They’re neither better than nor worse than the agents which they were manufactured to replicate.

 We’re talking about biosimilars now, and there’s a syntactic distinction which reflects a real distinction between biosimilar drugs and, then, plain generics for small chemicals. What’s the difference here?

Biosimilars were manufactured based on knowing the primary structure of the reference product without any other knowledge. And so, they’ve been reverse engineered. And that kind of knowledge has developed because of the 20 to 30 years of expertise in manufacturing biologics. So, this is a whole new idea where you start off with, simply, 1 piece of information, and you make the entire product to be highly similar to the reference.

 Highly similar but not necessarily identical.

 In 2014, there was a survey that revealed that biosimilars for rheumatoid arthritis were in the pipeline, but rheumatologists were unaware that they were in the pipeline. Why this disconnect? Why don’t people know that they’re coming or that they were coming?

 Well, I’m sure that was true in 2014, but a lot has changed since then. I think it would be very difficult to find a rheumatologist today who hasn’t heard the term “biosimilar.” Indeed, just this morning before coming to the studio, I got an e-mail from the American College of Rheumatology about their new Biosimilars Awareness Education Program. So, I think rheumatologists are aware of it (largely because the initial approvals were in rheumatology). I can’t speak to the awareness in gastroenterology and dermatology, which are the specialties which they use these products in. Gary, what’s your experience?

I can certainly speak to that. There’s certainly a heightened awareness at this point in time. Back in 2014, there was very little knowledge regarding that. The American College of Gastroenterology, the American Gastroenterological Association, the Crohn’s and Colitis Foundation, and a host of other different representative organizations have put out awareness educational programs, and, I think, the big issue that will face us is that of education.

 Back in April, a month prior to this broadcast, 2 drugs were approved—we’re talking about Inflectra and Renflexis. Are physicians aware that these drugs are now approved and they’re coming to availability? Do people know this?

 I think they’re learning that they’re approved and coming to availability. I think the fact is that there’s a gap between when the FDA takes a regulatory action and when the drug finally becomes available—a gap that can be at least 6 months and maybe even longer. So, the knowledge base is building out there, but there are still some misunderstandings that have to be corrected. For example, at some of the arthritis advisory committee panels last year, we heard people talking about additions to our therapeutic armamentarium&mdash;more drugs for patients. And, in fact, these are additional drugs, but they are additional versions of existing drugs.

Knowledge Gaps With Biosimilars

How will biosimilars impact our healthcare industry?

One of the issues about biosimilars is that they’re taking away the monopoly of a biologic. Now, there is a lot of money that is spent in terms of biologics and in terms of research and development. So they need to get a fair return on their investment. So what we have here is the issue of allowing for innovation, which then will increase consumer welfare—people benefit from these drugs&mdash;and at the same time allow for access to consumers but also allow for innovation of new drugs that will benefit society. One of the things that we see that is different from the generic market in the biosimilar market is that many of the brand-name companies are actually getting into the biosimilar market, so we’ll see competition more like brand-to-brand than we see brand-to-generic.

Joseph P. Fuhr, Jr, PhD, professor emeritus, Widener University, discusses the impact that biosimilars will have on the healthcare industry. 

Dr Joseph Fuhr: Biosimilars Bring on Brand-to-Brand Competition

How important is interchangeability for biosimilars?

Interchangeability is not important. There are 2 type of biologics: pharmacy, and physician-administered. In physician-administered, interchangeability will not matter, since the physician is picking the drug directly, so (there is) no need to substitute. In a pharmacy scenario, automatic substitution will occur, but are payers willing to pay a price premium for an interchangeable biologic? 

Biosimilars are highly similar, so how much better is an interchangeable biologic? It is highly, highly similar, so if (the) copay is greater for (an) interchangeable, then will patients pay more for it? 

Also, it costs more for an interchangeable study, since you need to do switching studies, which add to cost. So are firms willing to take on this investment with very little gain? There is 1-year exclusivity for interchangeables for each reference product, but other biosimilars will probably be in the market before this occurs. 

Also, some believe they may not be able to apply without some post-market data—which will delay entry&mdash;and not be allowed to apply initially for interchangeability. Also, if they don’t get approved for interchangeability, will this hurt the image of (the) product and (its) market share? There’s too much risk for too little reward to go for interchangeability.

Joseph P. Fuhr, Jr, PhD, professor emeritus, Widener University, discusses interchangability in biosimilars.

Dr Joseph Fuhr: Interchangeability Poses Too Much Risk, Too Little Reward

What will predict the biosimilar market share? 

Differences in various drug prices concerning various indications will depend on the number of competitors and how the originator responds to competition. If the originator responds aggressively by decreasing its price, market share of biosimilars may be low, but consumers benefit (from) lower prices and greater access. Market share is not the true metric; the real metric is how much prices have decreased in the market since biosimilars’ entry. And this underestimates the benefits, since (the) price of the originators would probably have increased without competition.

Joseph P. Fuhr, Jr, PhD, professor emeritus, Widener University, discusses biosimilar competition and its effect on market share and price.