 When we’re talking about the confidence in the biosimilar pathway and achieving biosimilarity, a lot of my colleagues and experts (in the biosimilars field) will discuss a biosimilar as being akin to a new batch or a new lot of a reference biologic drug. And the way we talk about that is we know that since 1998, when the first biologic in rheumatology was approved, that drug is different from the drug that’s coming under the same brand name now. It has shifted because of a change in manufacturing techniques (often improvements). We now know, with analytical detail and technology that’s available these days, that a biosimilar might be more like a current reference biologic than that reference biologic was similar to when it was started (when it was first FDA approved). And thinking of it in that light, you can consider a drug that has achieved biosimilarity status, according to FDA, as a new batch or a new lot of the reference product.

 I was just thinking that since you’re a specialist, that might be something that you would look one step further at (to figure that out). But for the average healthcare provider, they may be looking at this from the perspective of the history with small molecules, where you have a generic drug which has an exact ingredient that’s identical. They say that a pharmacy, or a pharmacist can actually make that substitution and that the interchangeable is really kind of the biologic version of that. Whereas, the biosimilar is just another product. So, in some ways, if you’re looking at it as somebody who’s not digging deeper, doesn’t it somehow make it sound like the interchangeable has been blessed by the FDA as being safer or substitutable for this product?

 Yes, I think that that’s certainly part of what some people are thinking. I think the FDA has made it very clear that that is not true—that it’s less safe because, of course, the hurdle for biosimilarity is where you determine whether the product has enough of the analytical similarity to be considered similar. But I definitely agree. There will be that perception, and I think that, in part, that’s why Europe doesn’t have the designation of interchangeability. And the reason for that is because they believe in the science of biosimilarity. They leave it up to the individual countries to decide. Hindsight is 20/20, right? We’re only 7 years in (in the United States), but I think that thinking that there could be a perception that an interchangeable is a higher quality product or has a higher level of safety or efficacy is incorrect. I think the FDA will continue to try and reiterate that. The reason why they’re 2 different designations is they’re approving 2 different things. It’s a worthwhile point because I think stakeholders, as they learn more about it, couldn’t actually go to that. And the truth is, it’s a different pathway and it’s a different approach from small molecules for many reasons, and the least of which is the complexity of the molecules.

Molly brings up Europe and I think that’s an astute observation. The difference between the biosimilar pathway and the interchangeable pathway is probably in the eye of the beholder, at this point. For me, biosimilar designation means that a drug is expected to work as well and have the same safety issues as the reference product. Like I said—a new batch of the old reference product. On the other hand, I think interchangeability is an excellent idea in the multi-payer, multi-state market (like in the United States as compared to Europe), because patients that I prescribe drugs for can be expected to move, change insurances, graduate into Medicare or their formulary, or their same old insurance might change year to year. They may actually expect to switch back and forth from a reference product to a biosimilar, so I’m thrilled that the FDA proposes to study drugs like that.

Videos

Biosimilars, Interchangeability, and Perceptions of Safety

 Dr. Worthing, we don’t have an interchangeable biosimilar on the market yet, but how would the designation of interchangeability affect you as a provider in your clinical prescribing practices?

 Great question. Molly is right—doctors and patients have been waiting, I think, for the interchangeability guidance. I think it would help build confidence. As a rheumatologist and somebody who writes prescriptions for biologics, there’s 2 general situations in which a doctor might write a prescription for a biologic. One instance is for a patient whom hasn’t taken the drug yet, and they’re new to the drug. And then, there’s the situation where we’re writing a prescription for somebody who’s already been on the reference product for some time, might have been doing well, and we’re writing a prescription for them (for the biosimilar) to change over and move. I think in the first instance, we’re getting a really good amount of confidence in the FDA pathway, which shows that the structure, and function, and anticipated usefulness, safety, and efficacy of biosimilars are biosimilar to their reference products. And to me, that kind of matches up with the first clinical situation&mdash;where I’m prescribing a biosimilar to a patient who’s not yet taking a drug.

Where the interchangeability pathway comes in boosting confidence is in that second situation—where a patient might be doing well on a drug and both the doctor and the patient are interested in knowing if a biosimilar (which might be cheaper or they might have easier access to it), is going to work the same way, not cause any more side effects, and still keep their disease under control. And that’s where I think the pathway that the FDA has drafted, which we saw this winter, really helps boost confidence. The pathway suggests a clinical trial design where manufacturers start patients on the biologic reference product and then switch 3 times (to the biosimilar, back to the reference product, and then back to the biosimilar), and confirm that they’re just as safe and effective. I think that will help (in that situation). We can be confident in telling a patient, “This drug might seem new to you, but it’s going to work just as well as the drug you’ve been taking.”

 That actually ties a little bit into a follow up question I was thinking of. You’re currently comfortable with the pathway. You’re currently comfortable with a patient (as you’re saying, kind of a new patient) and a new start with the FDA guidance. This is really about that switch patient (your continuing patient), and thinking about switching therapy. What evidence are you currently relying on (looking at products that have been approved) to make sure that you’re comfortable prescribing them?

 Right now, we’re looking at 2 different kinds of evidence, mainly. One is looking at analytical data. That’s data in the test tube, and data about the molecule and how it works, and looking at the mechanism of action to make sure it works the same way as the reference product. And then, the second kind of data is clinical trial data. Clinical trial data includes putting the drug into people who have the disease (where the drug is applying for indication) and making sure that it works just as well and has as few safety signals compared to the reference product. So, right now, we’re looking at those 2 kinds of data and judging that these biosimilars work just as well as their reference products.

 Can I ask a question, Angus? I’m kind of curious about this. As a first-designated interchangeable gets approved into the market, do you think this is going to be a tipping point, where because biosimilar uptake has been a little bit slower than anticipated, more physicians will be more likely to prescribe biosimilars? Or, do you think that they’re going to start saying, “Well, biosimilars are somewhat inferior to interchangeables,” and just ignore them because they don’t have switching studies? They don’t have the presentation studies and the FDA’s blessing.

 Great question, Ha Kung. I think that depends on a lot of variables. One is looking at how good the data is for that interchangeable. We want to see the data from clinical trials right in the FDA package insert. We want to know about them. All doctors, when they’re talking to their patients, should learn about the drug and how well it works. I think if that happens, and then on the payer side, people who are paying for the drugs (insurance companies, pharmacy benefits managers, the government), if they also see the value of the interchangeable drug, I think that we’ll get good market uptake. You were referencing how the biosimilars market hasn’t taken on as quickly as hoped. I think we’re all interested (from a provider’s and patient’s perspective), in getting the prices down. That’s all we’re talking about today with biosimilars—trying to reduce the prices. And really, that’s probably going to hinge on market uptake and getting more biosimilars into the market.

 Yes, and I would totally agree, Dr. Worthing. Coming from a manufacturer’s perspective, I think it’s very important that all stakeholders understand that a biosimilar that’s “just a biosimilar” is not less safe or less quality. It’s quite the opposite, actually. I think the bar for biosimilarity is high, to Dr. Worthing’s point around analytics, in particular. But, I think it’s going to be beholden for all stakeholders to understand that, in fact, a product with just a biosimilarity designation isn’t less anything. It’s different. If you pursue interchangeability, the purpose of that is different. Therefore, I think to Dr. Worthing’s point, manufacturers will look at things, product by product, and make that decision, which is a very significant investment. As Dr. Worthing mentioned, it’s a large-scale clinical trial. Because of the number of switches, it requires a lot of time. Therefore, it’s not an overnight proposition.

I think we’ll see some molecules in some markets where interchangeability is very important, and I think we’ll see other areas where it’s less important (because of how the product is given to the patient or in the disease area). If it’s for an acute use in oncology, I think you’ll see that things will look very different (from an interchangeability standpoint) versus in a chronic use, where a patient might be on it for years or decades.

Interchangeability and Rheumatology Prescribing Practices

 titled “Regulation, Policy, and Litigation in Biosimilars.” I am Amanda Forys, senior director of Reimbursement Policy Insights at Xcenda. Participating on our distinguished panel are: Ha Kung Wong, partner at Fitzpatrick, Cella, Harper, and Scinto; Molly Burich, associate director of Public Policy: Biosimilars, Pipeline, Reimbursement at Boehringer Ingelheim; and Dr Angus Worthing, practicing rheumatologist at Arthritis and Rheumatism Associates, and chair of the American College of Rheumatology’s Government Affairs Committee. Thank you so much for joining us. Let’s begin.

First, we’re going to talk about biosimilar regulation in the United States and Europe. The FDA is currently reviewing industry feedback on its interchangeability draft guidance. Molly, will biosimilar manufacturers seeking interchangeability have an effect on how reference product sponsors attempt to protect market share?

 That’s a great question. I think it will. I think the purpose of interchangeability, from an FDA standpoint, is really geared towards proving that switching products for any given patient will result in the same clinical outcome as the originator. Therefore, we believe that the designation of interchangeability will be meaningful. It will be meaningful from a patient standpoint. Hopefully, it builds their confidence in the product they’re taking. We really believe it will be meaningful from a physician standpoint, as the data will be built and designed exactly for switching. So, we think it will have an impact on behavior across the industry for those designations when they’re given.

 Yes, I’d like to also mention something about reference product sponsors (RPS). I think that to a certain extent, they’re really going to move to protect their products even more strongly because of the fact that interchangeables act like traditional small molecule generics. They can kind of piggyback on the marketing and education of the branded drug. And so, they’re going to look for ways to protect and get additional IP (intellectual property). And, I can see a lot more challenges from interchangeable manufacturers on IP that is owned by RPS. In particular, of the interchangeable guidance, they actually talk about how product presentation, for instance, including labeling, packaging, and delivery device design is actually really important and has to be looked at. And because of that, I can see reference product sponsors looking to get IP around those aspects (to kind of protect their market share as well).

 Yes, and that’s a great point. I think that the interchangeability guidance was probably the most long awaited guidance that the FDA released, as it pertains to biosimilars. There were industry, physicians—every stakeholder was really interested to see what the FDA was going to require. I think the reality is, it’s a high bar and appropriately so for what it’s trying to prove.

Biosimilar Interchangeability and Market Share

Former CMS head Andy Slavitt recently spoke about the need for a “champion” in Congress who can ensure sufficient budget allocation for healthcare. Do you agree?

I do, I think Andy Slavitt has a lot of good ideas about healthcare reform in the US. I think we do need champions in Congress right now to help fix the system. One important part, as we talk about biosimilars, is that we need to support the Food and Drug Administration as it hires experts that are needed to both review and approve safe and effective drugs—that’ll be biosimilars that we use, but also that will create guidances for manufacturers to come up with the right clinical trials and clinical trial designs to prove and give confidence to doctors and patients that the drugs work effectively. So, I think it’s important to fund the agency appropriately and we need champions in Congress to do that. Fortunately, this Congress has already authorized the Biosimilar User Fee Agreement of 2017, and the President signed it into law. So, that’s an important first step to that process.

Angus Worthing, MD, FACR, FACP, discusses the need for adequate funding for the FDA and healthcare. 

Dr Angus Worthing: Congressional Budget Allocation for Healthcare

FDA granted tentative approval to Merck for an insulin glargine follow-on pending the outcome of Hatch-Waxman litigation; does the fact that FDA regulates insulin as a drug have an impact on the litigation process?

I think it does. The Hatch-Waxman laws were enacted in 1984 and we’ve had a lot of practice with these litigations in the district courts and appellate courts, and the metes and bounds and contours of the Hatch-Waxman laws have been pretty well defined through decades of adjudication. It’s a pretty rapid and efficient timeline from [Abbreviated New Drug Application, ANDA] filing to final resolution of the appeal—pretty well-oiled litigation procedure. We have a lot more uncertainty with the [Biologics Price Competition and Innovation Act, BPCIA]. It’s a new statute, courts are just adjudicating it now for the first time, and we are seeing a lot of&mdash;I wouldn’t say confusion&mdash;but a lot of testing of the gray areas of the statute, for example, with 

. Litigants are really trying to take advantage of every perceived advantage in the statue and are bringing motions and are litigating those. So, the pace of litigation is likely to be quite a bit slower in the context of the BPCIA, at least initially. Also, we see a lot more patents typically being brought to bear in and BPCIA litigation. So, the fact that Lantus is being brought along this sort of well-oiled generic drug litigation track, I think [that] in general, although the specifics will vary from case to case, I think that in general that’s going to be a faster timeline right now, than BPCIA litigation.

Robert Cerwinski, JD, partner at Goodwin, explains why Hatch-Waxman litigation may provide a smoother path than does the Biologics Price Competition and Innovation Act. 

Robert Cerwinski: Hatch-Waxman Litigation of Follow-On Insulins

Oil States Energy Services v Greene’s Energy Group

 stand to change the IPR process in general?

It’s an interesting case in that there is a petition to the Supreme Court challenging the constitutionality of [inter partes reviews, IPRs]. IPRs have been one of the main tools in the tool kit of biosimilar applicants to try to clear a path for biosimilars to market. Everybody in the biosimilars world is watching this Supreme Court matter pretty closely. The upshot is, if in fact the law that created IPRs is governed to be unconstitutional, Congress is going to have to take another shot at either modifying or redoing the statute that created IPRs. So, the potential impact on biosimilar applicants from having the IPR scheme eliminated entirely will be quite significant. I don’t think anyone really expects IPRs to go away forever, but this is one of those cases where even if folks are feeling pretty comfortable that IPRs are at least in some respect constitutional and are here to stay, there is a risk that the IPR world as we know it could change in the near term—so we are watching it closely.

Robert Cerwinski, JD, partner at Goodwin, discusses a petition before the Supreme Court challenging the constitutionality of inter partes review. 

Robert Cerwinski: Oil States and the Inter Partes Review Process

Do pharmacy schools need to change their curriculum to address biosimilars? 

The pharmacy school curriculum should adapt to the growing increase in biosimilars by adding coursework to compare and contrast small molecules versus large, complex proteins, as well as approval process and requirements for bringing biosimilars to market. On rotation, pharmacy students should encounter biosimilars and have some experience with dispensing those agents.

Brandon Shank, PharmD, MPH, BCOP, Clinical Pharmacy Specialist, discusses the need for pharmacy schools to adapt their curriculum to address biosimilar treatments.

Dr Brandon Shank: Pharmacy School Curriculum and Biosimilars

Do “Pay-to-Delay” agreements affect biosimilars in the way they affect small-molecule drugs?

The FTC hasn’t really weighed in on that, and it’s really the [Federal Trade Commission, FTC] and the Department of Justice who have been driving a lot of the activity and the activism around pay-for-delay suits. The long and short is that policy is really kind of behind the Justice Department and the FTC’s concern about pay-for-delay. The basic proposition is that: We want to make sure that access to generic drugs happens as soon as possible, so we want to police settlements to make sure that the public is not being prejudiced by private settlements between generic drug companies and branded drug companies. The same policy rationale could very well exist with biosimilars. The policy behind the [Biologics Price Competition and Innovation Act, BPCIA] is at least roughly the same as the policy behind the Hatch-Waxman laws, which is: Let’s encourage early biosimilar entry by giving a mechanism for resolving patent infringement lawsuits prior to actual marketing—let’s incentivize both sides to get this dispute out of the way early, so that biosimilars can reach the market as soon as possible. So, because the policies behind the Hatch-Waxman laws and the BPCIA are roughly aligned, we may very well see some scrutiny by the Justice Department and the FTC of such settlements.

Robert Cerwinski, JD, partner at Goodwin, discusses the potential for government agencies to weigh in on pay-for-delay settlements in the biosimilars space.

Robert Cerwinski: Pay-for-Delay Settlements and Agency Scrutiny

Will there be reimbursement challenges with biosimilar products?

I think it’s too soon right now to say, exactly. It is a very complicated payer system, and there are a lot of incentives—for the hospitals, the patients, and the insurance companies. I hope that patients will see some of the cost savings, as well as insurances, and hospitals will be incentivized, hopefully, to add these agents on to their formulary and pass on the cost savings to the entire health care system both at a payer base and a patient-care level.

Brandon Shank, PharmD, MPH, BCOP, Clinical Pharmacy Specialist, discusses the potential for reimbursement challenges with biosimilars.

Dr Brandon Shank: Reimbursement Challenges With Biosimilars

What role will patient education play in the uptake of biosimilars in oncology?

I think it is going to be very interesting. I don’t think we know yet. I think that there is a question from a physician perspective and even a patient-centric perspective of how in-depth should a physician be. If the drug is approved, if the FDA has determined the drug to be not interchangeable but equivalent, and labeled for those indications, do you need to say more than the drug name and not the modifier that would identify it as a biosimilar? And I wonder if physicians will take that extra step, only because, is it patient-centric to do so? Are you going to convey to a patient risks that may not be there just because you’re defining a difference where the difference has been deemed immaterial?

Bruce A. Feinberg, DO, CMO, Cardinal Health Specialty Solutions, discusses the importance of patient education on biosimilar treatments. 