Part 1: Nabeel Khan, MD, Discusses an Infliximab Double-Switching Study

The Center for Biosimilars® (CfB): I’m Tony Hagen, senior editor with The Center for Biosimilars®. Today, we’re talking with Nabeel Khan, MD, an associate professor of clinical medicine with the University of Pennsylvania and an author of a retrospective, real-world study that demonstrated safety and efficacy for patients with inflammatory bowel disease [IBD]. They switched from reference infliximab to the biosimilar Renflexis, or from biosimilar Inflectra to Renflexis. The findings showed a high rate of continuation for patients on Renflexis. Findings from the study were presented at the American College of Gastroenterology 2020 Annual Scientific Meeting.

Switching patients with IBD is a difficult decision because you’re worried about the effects this might have on disease stability. Can you discuss these issues?

Khan: Sure. So, I think this is a relatively new area. So, that is one of the reasons why there is some apprehension, because it is relatively new and data oriented. The first big trial that was published was the NOR-SWITCH study, which looked at a very big cohort of patients with multiple different conditions, and the switch had to demonstrate a noninferiority of 15%, which was met.

Since then, there have been multiple different follow-ups on this [garbled]. So, there have been more biosimilars that have been introduced to test that. So, as time has passed and more data is coming out, it has become a little bit easier to switch patients on those products. Part of the aim of our study was also to show what the impact of switching was because a lot of the European data has shown that it is safe to switch.

So, we also wanted to look at that outside the trial basis—the NOR-SWITCH study was within the trial basis—so, we looked at it outside the trial basis to see what the impact was upon switching, and we found that it was quite safe to switch the patients, at least in our preliminary data. And we hope that with this there can be further utilization, within the states, of increased utilization of biosimilars, and all anti-TNF [tumor necrosis factor] drugs for that matter.

CfB: So, you've found that switching is safe, but what are the concerns among doctors and patients when they're presented with the idea of switching and the newness of biosimilars? What sorts of concerns come to their minds immediately?

Khan: So, I'm going to break it down [into multiple parts] One is the patients. The patients want to be stable on something and don't really want to switch. The inherent thing on that basis is that you're taking something away that someone is stable on. And as the old saying goes, if it isn't broken, why fix it? I mean [those that have switched] are stable. They're doing well.

Obviously, the biggest concern before switching is about the patient's stability and then, they're a little bit worried about whether a biosimilar will have the same effectiveness as the previous drug they were on. So, they are worried that the effectiveness of the drug may or may not be the same. Those are the questions they have. Then, they're also concerned about the side effect profile and whether they're going to get more side effects or whether they will get more of a drug reaction when they switch. Those are the predominantly major questions that do come up: efficacy and safety.

Physicians also have the same kinds of questions. They may not be comfortable with a patient being on [a biosimilar]. So, there's a reluctance to switch on that basis. And as long as [a patient] continues on [a reference product] and the patient is doing well, they think that there's not really much of a need to switch. And that is perfectly understandable. You have somebody who is doing well and is stable on [the reference product]. There's no harm in continuing them on that particular drug. And then, the other concern is what will happen to the immunogenicity, whether a patient will develop antibodies to the newer drug. And from that perspective, you may need to do multiple switches to see whether a patient will develop antibodies or not. So, those are the primary concerns. Again, efficacy and safety are the 2 basic issues that you will be looking at.

Also, what are the long-term consequences of it. This is a third concern that comes up because the data have all been relatively short term, so far. We don't know what happens in the long term. Anti-TNFs have been around for about 20 years and reference infliximab was introduced in 2000. In 20 years, there's been a good degree of data and there's a greater degree of, let us say, patient awareness. So, like with all new things, it does take some time, but in the end, our aim is to show what is the effect and what is the impact of the new change. We're not recommending whether one product or the other is better. We're just looking at what is the impact of the change and whether this is a viable thing to do or not.

CfB: These diseases are very upsetting to patients in terms of the symptoms that they develop, and this causes a great deal of anxiety, as well, for patients when presented with a possible treatment change or switch to a biosimilar?

Khan: It’s not a treatment change, so let's first discuss that. Generic drugs have been around for ages. The whole concept of switching from the original to the generic is not a new concept. That concept has been around for a while. The newer concept is that you're getting a biologic agent and now you're switching from originator to a generic biological agent. And because of the fact that these diseases, like you correctly mentioned, have a lot of potential to be, clinically, very debilitating and have long-term complications, patients are very concerned about that.

So, obviously patients are concerned about that and those are very valid concerns. And all educated patients have an idea of what exactly is going on, but this happens with every medical condition. Whenever you change an originator drug to a generic drug, people have questions about efficacy and safety. I think that can be extrapolated to patients with ulcerative colitis or Crohn disease, more so because they can have pretty significant clinical manifestations as well as long-term complications.

CfB: These issues are said to be a chief part of the resistance to using biosimilars. The VA has proven to be a good place to try a switching study. What is it about the structure of biosimilar use policies or formulary policies that has facilitated a study like the one you have done?

Khan: The facilitation of this in the VA was not based so much on policy but on the VA's centralized pharmacy benefit management system. So, if you want to do a study, you have these 9 million veterans who fall within the VA health care system. You have a record of all the medications that they're on and you have long-term longitudinal follow up. So, if you were to try to do a study in the private sector, it would be difficult because you are pulling information around from here and there.

Now, the other thing is that you can individually look at all the records to see what happened to the patient because there is so much research that is done in the VA. The VA's record system is so comprehensive, and it is shared nationally. Like I can look at a record of somebody who lives in California to see how he did after the switch was made.

Now, obviously you cannot do this within the private sector health care system because you can't access somebody in a capital health care system. [For example,] we cannot look at Kaiser Permanente's health care system and see what happened to those patients individually after switching. You may have some official medical records data on that, but they are not very granular, where you can go into every individual patient's chart and really see what exactly is happening to them.

So, that is why the VA is very good for doing this kind of research, because of the fact that you have all this data that is recorded. Especially with infusions, patients have to come in and get those infusions. So, you know exactly what is happening to those patients because they’re coming in every 8 weeks, or 6 weeks, or whatever regimen they're on. And then, you can see the impact of the change on that. So, you could probably see these kinds of things outside of the VA, but because of the way the electronic medical record system is set up and the commitment to develop this electronic medical record system for researchers to evaluate what is happening across the nation, it's easier to look at this within the VA.

CfB: Records are very important for your study, but so are policies that encourage doctors to use biosimilars. Could you have done a study like this on the private side or not?

Khan: So, let me clarify, it's not that they are encouraging all doctors to switch people. The VA is very open to letting the doctors do what they want to do. The availability and cost savings associated with biosimilars is pointed out to doctors. And if they feel their patient can be placed on that product, they can voluntarily do that. It's not something that we are forced to [do]—let me clarify that. There is no coercion in the VA. The VA does what is best for the patient and for the patient's care.

With every new drug that does come out, the VA will educate physicians that there is a new drug and that if they feel that this can be a safe substitute for their patients who are on another therapy, then they can switch them. If they feel it is not safe, then they don't have to do that. It is not that the VA is forcing every patient to automatically change over to this drug. It is a decision that is made literally between the physician and the patient. They decide whether they are going to go ahead and do that or not do that. And if both parties decide not to do that, there is no portion of the VA that says, "No, you have to do that."