Hi, I’m Skylar Jeremias for The Center for Biosimilars®, your resource for clinical, regulatory, business, and policy news in the rapidly changing world of biosimilars.

Here are the top 5 biosimilar articles for the week of January 18, 2021.

 in a study of hypertension and proteinuria in 75 patients treated with bevacizumab reference vs biosimilar products, investigators reported at the ASCO Gastrointestinal Cancers Symposium 2021.

Number 4: Switching patients with inflammatory bowel disease (IBD) from the CT-P13 infliximab biosimilar to the SB2 infliximab biosimilar appears to be safe and effective whether 1 or more switches between biosimilars and the originator product were involved, 

Number 3: Investigators have demonstrated that 

 of the first bevacizumab biosimilar (Mvasi, Amgen) in the United States was strongest for patients receiving treatment for metastatic colorectal cancer (mCRC).

Number 2: Sonia T. Oskouei, PharmD, BCMAS, DPLA, wrote 

 on why ophthalmology biosimilars are a therapeutic area to watch in 2021.

 at the International Generic and Biosimilar Medicines Association (IGBA), Celltrion, Innovent Biologics, and Kamada.

To read all of these articles and more, visit 

Videos

The Top 5 Biosimilar Articles for the Week of January 18

Here are the top 5 biosimilar articles for the week of January 11, 2021.

Number 5: Rapid health care reforms in China have led to a regulatory environment that 

 for biosimilar development and approval, according to Lawrence A. Hill, PharmD, MBA, RPh, BCPS, CEO of Gan & Lee Pharmaceuticals

Number 4: Authors of a review of studies on machine learning speculated that 

 could improve the selection of biosimilars for therapy.

Number 3: Investigators have reported pharmacokinetic (PK) findings that 

 of Viatris’ trastuzumab biosimilar candidate (Ogivri) to reference Herceptin.

Number 2: Authors of a review found that biosimilar uptake and market share are 

 to establish whether these agents will lead to savings.

Number 1: Multiple biosimilar developers have obtained FDA approval for adalimumab biosimilars but won’t be able to enter the market until 2023. One 

 is whether these approved biosimilars will still be relevant 2 years from now.

The Top 5 Biosimilar Articles for the Week of January 11

The Center for Biosimilars® (CfB): I'm Tony Hagen, senior editor for The Center for Biosimilars®. Today, we're interviewing Charles Bennett, MD, PhD, a hematologist and oncologist and also a professor in the Clinical Pharmacy and Outcome Sciences Department of the College of Pharmacy at the University of South Carolina. Dr Bennett served as the lead author on a recent paper about the progress of oncology biosimilars and how well accepted they've become.

In part 1 of this interview, we talked about how the FDA measures median time spent on biosimilar application reviews and whether that's an accurate way to do it. We also talked about the rigorousness of FDA reviews in comparison with those in the European Union and Japan. Multiregional regulatory reviews were a key element of Dr Bennett's paper. We also talked about doctor acceptance of therapeutic biosimilars vs supportive care biosimilars.

 One important point [I want to mention] before we get to the first question on the table, is the time to approval. I know this number is very controversial. One of the things that the FDA says is that they approve these biosimilars within 12 months. So, why is my mean time 1.3 years in this paper? The FDA told me, "No, we have not done a single 1 in less than 12 months because we got the User Fee Act and we've adhered to the User Fee Act.”

I only give you credit for when you pass the test, not when you take the test. So, if you take a test, which is [a response in] less than 12 months, and they flunk you, which means that they give you complete response letter and tell you that you have to reapply, I keep the clock going. I think the median time that we should look at should be from the time when you submit your initial dossier to when you get an approval, as opposed to what they use, which is the initial time to submission to their initial decision on that, regardless of whether it's positive or negative. I think that's more a relevant value. The United States, as you saw, has a tremendously high fail rate. So, every time you fail, you're hurting that median time because they don't give you just 1 day to re-turn your homework in.

In the UK, they have some fails. And in Japan, they have no fails. It affects the median time to acceptance of the drugs by the regulatory authority. For some of the US drugs, the whole time from start to finish could be 4 years if you fail.

CfB: Who's making this argument that that median time should be calculated differently? Is it the manufacturers?

 The FDA makes it. They are being paid to make sure that the time that they take to approve a biosimilar is 12 months or less. They have a [Prescription Drug] User Fee Act, which says they can do it [in that time]. Then, you get people reading [my paper], and it's not less than 12 months. Then, they're upset because they want to know how come I can't count, but I made an internal decision that [we were going to study] between the time you start to test to the time that you got a passing grade. I don't know, for instance, whether the FDA, if you flunk the test, or you get a complete response letter, makes you pay a second user fee to get your revised application in. I suspect they don't. I suspect they give you a 1-time user fee and you do it till you get it correct.

CfB: Well, that's interesting, because the FDA is trying to revise its user fees so that it has enough money to cover the costs of reviewing these applications. And if it flunks somebody and they have to come in and do a more involved review following that, it's going to drive up their costs. So, are the user fees actually going to cover the expenses involved?

 I think it's important to get it correct on your first try, and it's just like a student. You certainly don't want to take a final exam, flunk it, and have to take a retest. And these are bigger scales. The fact that we put it up there pretty heavily and went into detail about why they flunked the test really raised a strong concern about this. And that's one of the kinds of questions we have about a barrier that I think exists—the flunk rate in the US was significant. It was less so in Europe and not at all in Japan. We could just be much harder graders, maybe. But at the end of the day, it definitely takes its toll. And there should be some education between the FDA and these biosimilar applicants, because you can't live with a 44% flunk rate. My kid wouldn't even be able to graduate the next year of high school with a 44% flunk rate. This is what the FDA does.

And then, if you ask a provider to be comfortable with a biosimilar and say, "Are you happy with a drug that's gone through this FDA application 2 times in a row and is now on your desk for use at a 30% discount, at a 10% discount, or a 20% discount?” And that's where I don't think the educators are being realistic.

CfB: Well, do you think that the flaws are in the application that's being put together, or are the flaws are in the molecule itself?

 If you look at the table that we went through—Table 2 on what the flaws were—they were clear in some of these cases. Some of the cases [had to do with] manufacturing. [The FDA] went through a manufacturing plant and they didn't like the way the plant was [set up]. For Pfizer, they were told 3 times that their plant was not up to speed. The Pfizer people were hard-headed about it and sent in their application. Then, they were shocked when they got a rejection that said that their plant wasn't up to speed. They had already received 3 letters telling them that the inspectors went through and didn't like that the plant was not clean and not appropriate for manufacturing. And that's a big part of it. One of these was a failure on a clinical trial. A clinical trial was supposed to have a preset limit of where [the biosimilar was supposed] to be about the same and it ended up outside the limits.

So, I think a lot of it has to do with the manufacturing when these complete response letters come out. And I don't see as many complete response letters or not-approved letters in England coming out with concerns about manufacturing, which suggests to me that the manufacturing reviewers for the FDA have a different checklist than the manufacturing reviewers in England and Japan.

CfB: How thorough is the FDA review process compared to the reviews in the UK and Japan?

 I have to say, the question really is, is the FDA too cautious or are Europeans too liberal? That's the way I look at it. And it looks to me that if you're really focusing on manufacturing, and you have manufacturing experts on the review team, and they find [problems], I think that they're the real deal. In fact, look at the manpower we have at the FDA vs the manpower they have in the MHRA [the Medicines and Healthcare products Regulatory Agency (United Kingdom)] and in other places. We have a huge amount of manpower. And I think they go in there and they kick the tires pretty good. And many times, there are manufacturing concerns. And I saw that there would be applications that go through Europe, as a European biosimilar, that would have no complete response letter. And the same drug would come to the US and get a complete response letter, for quality. So, if you ask me, they're doing it side-by-side. And they’re just giving the Europeans a pass and the US a failure. That leaves you with some hesitancy to use the drug.

When you ask about the barriers and why aren't these things taken out, I think that one thing needs to be clear: They have to improve that pass rate. They've got to do a better job of getting through without getting rejected; otherwise, people at the [reference product] company are going to say, "Your biosimilar just got rejected for quality reasons. Good luck, pal."

CfB: Well, there’s the issue about whether regulators and individual countries should accept trial evidence that was gathered outside the country. Manufacturers say that it would streamline the process if that were done. But you've found that, in some cases, regulators are saying, "No, we want these trials performed in the country." It seems that there might be, based on your statements, some merit to maintaining this system of having in-country evidence only.

 So, one point there, just to be clear. I'm talking about manufacturing facilities only. If you look at my paper, with these drugs, companies that do phase 3 trials that try to show [biosimilarity], we found that they were done, oftentimes, in 50 countries. Now, I don't know for a fact if the FDA goes to visit all 50 countries to look for the primary data. I can't imagine they do. I think that they do a lot of these studies in Eastern Europe. I don't know. I've been to Eastern Europe for a holiday, but I've never been there in any official capacity. I don't know what it's like in terms of putting these patients on clinical trials in Eastern Europe. They may have 1 or 2 patients per country in several of these countries.

The reason why [biosimilar developers] do that is that they want the drug to get regulatory European-wide approval, and they want each country to have the ability to start using the drug. One of the ways is that each individual country gets some experience with the drug in the clinical trial.

CfB: It's said that doctors are, in many cases, leery of using biosimilars, and that's attributed to a lack of education, that doctors have not been properly educated on the value, efficacy, and safety of biosimilars once they're approved by the FDA, and that they ought to have higher levels of confidence than they do. But you're saying that there may be some justification for hesitancy to use biosimilars in the United States?

 There's a conceptual framework here between the supportive care drugs and the therapeutic drugs. Patients and doctors have a better level of comfort with the point-of-care drugs like GCSFs [granulocyte colony-stimulating factors] than they do with Rituxan [rituximab], Herceptin [trastuzumab], and Avastin [bevacizumab]. So, I think the education and the comfort for the use of [polyethylene glycol] and epoetin alfa is very high.

I just say that I've got 1 form or another of supportive care drugs, I'm good with that. And then, you get down into the backbone of the treatment for these patients with cancer. Say you've been [treating] a patient who's got follicular lymphoma and they've been on Rituxan for years. And then you decide “I'm going to switch to biosimilar rituximab because the payer said so.” Sometimes the doctor says, "Look, I've got 10 good years in on Rituxan. I'm not comfortable with someone switching us to use biosimilar rituximab when I see no need to, except for the economics of it." It used to be that when the patient went to the pharmacy and picked up the generic, they'd go crazy because they would say that they had been on a thyroid pill for 10 years and now they're getting a generic thyroid drug. I think therapeutic care is different than supportive care. I make that difference.

CfB: Manufacturing facilities are where the red flags have been raised, but the biosimilar processes have to be maintained very, very carefully all the way through, even for the originator products. Could this be a monitoring issue, as well as a setup issue, for biosimilar development?

 Yeah, there's no doubt. But I will say, for instance, Rituxan has a long history of drift over time. So, the Rituxan that they use today is different than the Rituxan used before. And there have been periods of time where the drift is so large that they had to have a reset. And that happens with production in particular. So, people have talked about that, and many people say there's no difference between a biosimilar and a biologic reference drug. But what you see today is not what you will see tomorrow. I've never seen a complete response letter like this for any of the major reference drugs at all. I think that when the reference drug comes on the market, you're pretty clear that the GMP [good manufacturing practice] is up to speed.

Charles Bennett, MD, PhD, a hematologist and oncologist and professor in the Clinical Pharmacy and Outcomes Sciences Department of the College of Pharmacy at the University of South Carolina, discussed the FDA’s pace of biosimilar approvals and the findings from his recent study.

Charles Bennett, MD, PhD, Discusses the FDA’s Biosimilar Approval Timeline

Number 5: China’s National Medical Products Administration (NMPA) has approved Innovent Biologics’ adalimumab biosimilar (Sunlino) for 

 using Mvasi, a bevacizumab biosimilar, for all indications of the reference product (Avastin), reviewers stated.

Number 3: Product differentiation by concentration 

 to the multiple adalimumab biosimilars approved but not yet launched.

 with expansion of its Reykjavik, Iceland, facilities to speed up development and put the company on its way to launching its first biosimilars.

Number 1: A study of uptake of the trastuzumab biosimilar ABP 980 (Kanjinti) in Europe found 

, according to an abstract presentation at the 2020 San Antonio Breast Cancer Symposium.

Here are the top 5 biosimilar articles for the week of January 4, 2021.

The Top 5 Biosimilar Articles for the Week of January 4

To watch part 1 of this interview, click 

The Center for Biosimilars® (CfB): I'm Tony Hagen, senior editor for The Center for Biosimilars®. Recently, we spoke with Ivo Abraham, PhD, RN, a professor with the University of Arizona Health Sciences in the Department of Pharmacy Practice. He is also a health care consultant with Matrix45, which he co-founded. In this part of the interview, Abraham discusses how the use of pegfilgrastim biosimilar is likely to be affected by the current spike in the COVID-19 [coronavirus disease 2019] pandemic.

As we enter the second significant wave of COVID and hospitalizations soar, it's important for patients with cancer to stay out of the hospital at all costs. What do you see happening with these pegfilgrastim dynamics during this phase of the pandemic?

Well, as long as we're under pandemic conditions, it's going to be very difficult for biosimilar manufacturers to compete. And we're going to see a continuation of price erosion. On the ASP [average sale price], the challenge then goes back to what are the pathways that we should follow?

The thing we can learn from other parts of the world is whether [pegfilgrastim] necessarily needs to be administered in a cancer center. When my sister was recovering from breast cancer in Belgium, she could go to her GP (general practitioner) down the street in the village and get her injections. This was supervised by the cancer center. In other countries, home health nurses come in to do the rounds. And that is easy to implement in places where people live close together. You can have the home health nurse go without spending much time traveling. For patients who live farther away, [they can use an] on-body injector.

CfB: Although you can potentially save money from using pegfilgrastim biosimilars, as your studies project, is that money really available to providers to apply for the treatment for individual patients or are those savings really going to the payers, or to the manufacturers? Who really benefits from those savings?

The direct beneficiary is a payer. [garbled] Taxes, employee contributions, employer contributions. Ultimately, the savings affect the payer and very indirectly affect those of us who contribute to the pool of money. That being said, the important aspect is that we need to put pressure on the payers to use that money, those savings, in a meaningful way.

Now, there's a challenge there because the private payers are publicly owned companies. So, for them, and I'm oversimplifying, it might be good to have better results or show cost reductions and all of those good things. Another element that is important in this regard, is that, for instance, CMS is experimenting with and implementing certain programs that financially incentivize the provider organizations. For instance, the Oncology Care Model. In the Oncology Care Model, one element is your drug budget and bringing that within certain parameters. So, when converting to a biosimilar, if there is a price difference, it helps you with that. There's a benefit for the provider organization in the sense that their drug budget goes down. As a provider with your savings, you should be using that in a responsible, ethical way, and you could say, "We're going to allocate some of those savings or all of those savings to patient-centric services or buy more drugs that otherwise we would not be able to buy."

What we're now beginning to elaborate on with ACCC [The Association of Community Cancer Centers] is how could that be used for patient-centric services? Patient-centric can be very simple [such as] transportation support, especially for long distances. It can be nutrition support. We do know that a lot of cancer patients are paying so much out of the household budget that there is a certain degree of food insecurity. It could be with financial navigation services. So, from a payer perspective, you could end up providing even better care to your patients and help them thorough one of the toughest periods in their lives. There is an enormous opportunity there, especially with incentive programs, for providers to benefit as well.

Ivo Abraham, PhD, RN, a professor with the University of Arizona Health Sciences in the Department of Pharmacy Practice and a health care consultant and co-founder of Matrix45, discussed how the pandemic is likely to impact the use of pegfilgrastim biosimilars.

 Part 2: Ivo Abraham, PhD, RN, Discusses the Pandemic’s Effect on Pegfilgrastim Biosimilar Use

Here are some of our most-listened-to 2020 "Not So Different" podcasts.

Anurag Rathore, PhD, coordinator of the Center of Excellence for Biopharmaceutical Technology in Delhi, India, discusses findings from his study on

Ryan Haumschild, PharmD, director of pharmacy at Emory Healthcare in Atlanta, Georgia, explains how a series of steps helped to increase biosimilar utilization within the Emory system and how these initiatives could be 

Ha Kung Wong, an intellectual property law attorney and partner at Venable Fitzpatrick in New York, New York, and April Breyer Menon, an expert on biosimilar patent law and founder of April Breyer Consulting in Chicago, Illinois, discuss 

 to improve biosimilar uptake and their chances for passage.

Christine Simmon, executive director of the Biosimilars Council and senior vice president of policy and strategic alliances at the Association for Accessible Medicines (AAM) in Washington, DC, discusses some of the 

 the organization is looking to advance and their chances of approval.

Lastly, we spoke with Adrian van den Hoven, director general of Medicines for Europe, and Diogo Piedade, market access manager for Medicines for Europe, about their 

 for biosimilar access and what European markets they feel need the most work.

To read all these articles and more, visit 

The Leading “Not So Different” Podcast Episodes of 2020

Here are some of our most-popular biosimilar interviews for all of 2020.

Soumi Saha, PharmD, JD, senior director of advocacy at Premier, discusses 

 caused by coronavirus disease 2019 (COVID-19) and policy recommendations that could fix the problem.

Gillian Woollett, MA, DPhil, senior vice president, Avalere Health, explains potential consequences if the United States were to 

Will Gatziolis, MBA, an associate principal at ZS, explains how the COVID-19 pandemic 

 and what manufacturers can do to take advantage of this opportunity.

Sheila Frame, the vice president of marketing, market access, and patient services at Sandoz, discusses US biosimilar policies in development and the 

, at the World Biosimilar Congress 2020 at the Festival of Biologics USA in San Diego, California.

An additional interview features Byoungseo Choi, head of marketing for Celltrion Healthcare, who discussed how Celltrion's infliximab biosimilar can 

 of COVID-19–related inflammation, as well as the company’s launch plans for biosimilars through 2030

The Most-Popular Center for Biosimilars® Interviews of 2020

Ivo Abraham, PhD, RN, a professor in the Department of Pharmacy Practice at University of Arizona Health Sciences, and a health care consultant with Matrix45, discusses 

 that demonstrated savings for pegfilgrastim vs the on-body injector.

CfB: I'm Tony Hagen, senior editor for The Center for Biosimilars®. Today we're talking with Ivo Abraham, a professor with University of Arizona Health Sciences in the department of Pharmacy Practice. He's also a health care consultant with Matrix45, which he co-founded. Abraham was coauthor of 2 studies of pegfilgrastim biosimilar versus the on-body injector [OBI]. He and other investigators sought to measure the savings potential for patients with non-Hodgkin lymphoma and diffuse large B-cell lymphoma. Abraham said the study findings could be used as a bargaining chip to obtain bigger discounts from manufacturers.

When do you use pegfilgrastim, and for what reasons, and how often?

 It's a very common part of cancer treatment. You need to take into account that a lot of chemotherapy regimens are highly myelotoxic. They suppress the bone marrow, which means that we do not efficiently produce red blood cells and white blood cells anymore. White blood cells protect us from infection. So, if you have a patient who's being treated with a highly myelotoxic regimen, that patient is at risk for neutropenia. The drop in white blood cells exposes that patient to other risks of infection and febrile neutropenia, which usually leads to hospitalization. And there's also a very significant mortality rate. So, the great innovation—it was truly an innovation that Amgen did first with Neupogen, the precursor to Neulasta—then later on in 2002, I believe, with Neulasta—was really to stimulate the production of white blood cells, and it helps patients who receive a highly myelotoxic chemotherapy regimen with that drop in their white blood cells, in their neutrophils, so that they can go back up.

We have seen that over the years a very significant reduction in mortality, even without febrile neutropenia [FN] or severe neutropenia. And it's obviously indicated for patients who receive what we call highly myelotoxic FN—febrile neutropenia risk greater than 20%. There's also a middle category of 10% to 20% myelotoxic regimens, where if patients have a risk factor, the US guidelines, the European guidelines, will say those patients should be considered for prophylaxis with Neulasta, or similar products—growth factors. There’s a few in addition to biosimilars.

CfB: What is the difference in cost between pegfilgrastims? How much can you can you save with biosimilar products?

 Well, the absolute savings depends on a number of factors. First of all, if it is for CMS, for Medicare, predominantly, those costs are publicly posted. And that is the average sales price (ASP), as we call it. Also, don't forget that 45% of cancer patients are not over the age of 65. They’re younger than 65. So, they're more likely to be insured by commercial payers. So, the issue is what do the payer and the manufacturer negotiate? The payer may also be a pharmacy benefit manager. And those things we don't know. We have certain indicators, something called the WAC—the wholesale acquisition cost. The average wholesale price gives us an idea of what this might be, but this is before rebates, and discounts, and everything else that gets negotiated behind closed doors. Now, one element that is important to point out is that for Medicare—now we're talking about the average sales price, the ASP, which is issued on a quarterly basis—and it's a pretty complex calculation. But it has the benefit of taking into account all of the discounts and rebates and price reductions that are allowed or that are given by the manufacturer for their drug. That may be for your reference product. So, that may be Amgen, that may also be for the biosimilar product. The interesting part with the ASP is that it is eroding the price differential between biosimilars and the reference product. In fact, we were just calculating or checking on the Medicare website, the CMS website, what the new numbers are that have just been released. And now we're seeing that not 1, but actually 2 of the biosimilars, with the ASP, are now more expensive than the reference products. That is for, let's say, roughly 55% of the patients of that class. And so, that price differential is eroding. Where it is not eroding is of course, on the commercial side, which is very significant. Also, those prices tend to be higher than those that are negotiated by CMS.

CfB: Let’s go to your studies and the settings and why you decided to do them.

 Well, we have been working in this line of work for the past 11 years. Actually, we have been doing biosimilar work since 2008, 2009—originally in Europe. How did that come about? People that we used to work with on growth factors, also red blood cell growth factors, had been recruited by up-and-coming biosimilar companies, when the first ones came to Europe, which was about 10 years before the United States. So, we've been working with them from the very beginning. We did the early studies on price comparisons for the European G5 countries. You know, if you convert to biosimilar, from 100% down to 10%, how much savings will you generate? Now, let’s be honest. That's not rocket science. If one product is cheaper than the other one, we can show their savings and how these savings accrue. But we then started thinking—and now we're talking 2012—it’s nice to have these savings, but what do we believe should be done with those savings? And that's when we started looking at this notion of expanded access.

Think of your home budget. You're able to save something, so you now have some freely available cash. You could put that to some other use, and you will put it to some useful use. The argument that we were trying to make is, this is also the time that we're seeing very good and very expensive cancer treatments coming on the markets. Then biosimilar conversions provide a way to shrink our growth factor budget. We can take that money and reallocate it totally on a budget-neutral basis to a payer to provide more patients either with more growth factor, or especially, with expensive cancer treatments.

CfB: What did you learn from these studies?

 Several observations are important. First of all, and it's an observation or a question: To what extent are payers really thinking along those lines? We're picking up signals that they're saying, “Here's an interesting argument. Here is where we could also provide a service to some extent—we could change our plans in such a way that more patients would be eligible, with a lower co-pay threshold for certain of these treatments.” That's the first important element. The second important element is that we never really know what is negotiated behind closed doors. So, we have to create scenarios where we put it on a curve from 10% conversion to 100% conversion. We may also put it on cost curves and see how those curves interact. That issue, ultimately, is these calculations are not difficult to replicate. And it creates a bit of a framework, maybe a platform, so to speak, where also payers can start looking at, if we now go for this particular health plan that we have with this biosimilar, or reference product, we can go negotiate with Amgen and see how far they're willing to lower the price, which Amgen has been doing, Rightfully so. So, that is an important aspect. But what has really begun to surprise us in the last few months is this erosion of the differential between biosimilars and the reference products, with regard to pegfilgrastim. And that is important, because of 2 reasons: First of all, the way the negotiated prices and negotiated contracts will evolve. It's probably more like what we have seen in Europe and other parts of the world where you put in your bid with the United Kingdom, for instance, the National Health Service. In other countries with a totally single payer system, the government payer agency, so that it's no longer going to be the marketing strategy of, “Let me go out and capture hospitals and health systems and cancer centers who want my product.” That will still continue a little bit. But, how can I as a biosimilar manufacturer or as a reference product manufacturer go negotiate with certain groups and put 2-, 3-, maybe even 5-year contracts in place, and in that way, secure my markets, market position. You can take the findings on cost savings and how this can pay for additional care and use those as arguments to coax greater discounts from the manufacturers.

And for instance, it is known that Amgen and UnitedHealthcare negotiated a deal for Neulasta. And I think that is totally appropriate. Sometimes, the perspective is, it's us against them. But it's also us among each other, because here we are coming on the market, now, with our biosimilar pegfilgrastim. There is an aspect here of not all manufacturers competing against each other. And we need to take into account that, historically, the biosimilars came from small companies who then sold their biosimilars to the larger ones—Sandoz, Novartis, Pfizer—and the larger companies have really acquired molecules from smaller, almost mom-and-pop laboratories. I don't want to minimize it, but very small laboratories say “OK, let's try to create [a biosimilar].”

CfB: So the OBI fails occasionally, and that's a reason why a doctor might want to use a straightforward pegfilgrastim—biosimilar or reference product. So, how does it fail? And tell us about whether providers are aware of these issues.

 Well, the failure can be related to a number of factors. It can be device failure, or there have also been instances of a user failure. You have a restless night—you know, somehow it comes off, whatever. And let me preface it by saying that our focus on the on-body injector failure is not meant as a way of promoting biosimilars. In fact, the OBI injector is a phenomenal concept. And there are 2 elements here. First of all, it has to do with when should pegfilgrastim be administered, or the standard filgrastim. And historically, also, according to the label, it has to be done between 24 and 72 hours after the end of chemotherapy. Now, that works, if everybody lives close together, close to a cancer center. You could go in the next day to get your shot. Increasingly, and actually, the first major set of studies were done by [Howard A. 

 III], the issue of same-day administration of filgrastim, pegfilgrastim. Really, you're there for your cycle infusion, and at the end, everything is finished. At the end, when everything is finished, they also give you your pegfilgrastim. There are some physiological reasons why that should not be done. It may interfere with the formation of the cells, etc. So, the safe practice is, wait 24/28 hours. And then administer. On the other hand, there's also a lot of evidence that same-day administration with pegfilgrastim might be safe. And that is growing. So, that is one element that we need to take into account, this issue of same-day administration, which you know, is done also in part for patient convenience. Now, if you live in Manhattan, it's a cab ride to your cancer center. If you live in Arizona and you live in Yuma and you’re being treated in Tucson, that's several hours in the car. And these are patients who are already very sick, very fatigued. So, there’s the additional cost. Maybe you stay overnight. There's a lot of patient convenience aspects, and that's why the National Comprehensive Cancer Network (NCCN), in their guidelines, even in last year's, or maybe even the one the year before, have already started saying, or hinting, if it is for patient convenience, distance, etc, same-day administration, the framing might be OK. So, that's an important element that affects Neulasta, that affects any of the biosimilars.

The beauty of the OBI injector is, of course, you can go home and 27 hours later, or thereabouts, you will get your prophylaxis, which is very important, as we know. The failure rates kind of surprised us and the literature is very young in that regard. OBI failure ranges from 1.7% to 6.9%, thereabouts. Let’s say 2% to 7% reported failure rates. No doubt, the next generation [product] will be improved in that regard. But the consequence is that patients don't have that protection against their drop in neutrophils. They’re exposed to infection and face hospitalization. According to the Centers for Disease Control, it’s over $30,000 for hospitalization for neutropenia. And the death rates, which according to Dr Lyman from the Hutchinson center in Seattle, is around 37% to 38%; so, that's a very high mortality rate, which is preventable.

Now, another reason why we should be concerned about device failure is COVID-19, and ASCO and NCCN and some other groups have come out with the idea that we should reduce patients coming through the cancer center. You need to have protocols to reduce the traffic. We certainly want to keep patients out of emergency rooms, for obvious reasons in the COVID-19 era. So, their advice has been either do same day, or probably safer and better, use the OBI. But then, of course, we need to make sure that this is not a patient who is going to have a device that fails. What clinicians should do is really educate patients and their caregivers, whoever accompanies them to do the chemotherapy. But what are the signs the signs that things are not going well? And in that case, you need to act immediately. Call us. Patient education, counseling, and caregiver counseling become very important.

CfB: What kinds of things can you do to ensure that the OBI is going to work as hoped for?

 Well, it's like any appliance. It has failure rates. And I'm sure that the engineers at Amgen are working very diligently on that.

CfB: So, you feel that doctors generally are aware of these issues and take them into account and have full discussions with patients?

 Actually, I don't have data on that. But I'm part of some discussions with the Association for Community Cancer Centers, which provides care for two-thirds of the cancer patients in the United States. There is increasingly more attention to discussion, or facilitating discussion between clinicians, but also office staff—the finance office—about the biosimilar dialogue.

Part 2 will be available to watch after January 1, 2021.

Ivo Abraham, PhD, RN, a professor in the Department of Pharmacy Practice at University of Arizona Health Sciences, and a health care consultant with Matrix45, discusses recent studies that demonstrated savings for pegfilgrastim vs the on-body injector.

Part 1: Ivo Abraham Talks About Biosimilar Pegfilgrastim Savings Amid COVID-19

Here are the top 5 biosimilar articles for the week of December 14, 2020.

Number 5: Studies of trastuzumab biosimilars in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer have yielded 

, according to presentations at the 2020 San Antonio Breast Cancer Symposium.

Number 4: Investigators studying biosimilar savings and use rates in HER2-positive breast cancer observed dramatically 

 of trastuzumab biosimilars and said payer policy appears to have contributed to higher biosimilar utilization.

Number 3: Celltrion’s high-concentration, citrate-free adalimumab biosimilar candidate (CT-P17, Yuflyma) has 

 for marketing authorization by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).

Number 2: Sarfaraz K. Niazi, PhD, an advisory board member for The Center for Biosimilars, published an 

 on Boehringer Ingelheim’s recent filing of a citizen’s petition asking the FDA to change its interpretation of the term strength in the Public Health Service Act.

Number 1: Biocon Biologics and Mylan have received a 

 from the EMA CHMP for the marketing approval of their biosimilar insulin aspart candidate (Kixelle) for the treatment of type 1 and type 2 diabetes.


The Top 5 Biosimilar Articles for the Week of December 14

CfB: Hello, I'm Matthew Gavidia. Today on MJH Life Sciences Medical World News, The Center for Biosimilars® is pleased to welcome Jennifer Snow, vice president of Reimbursement and Policy Insights at Xcenda, part of AmerisourceBergen. Great to have you on Jennifer. Can you introduce yourself and tell us a little bit about your work?

 Pleasure to be here today. So, my name is Jennifer Snow and I’m vice president of Reimbursement Policy Insights at Xcenda. I lead a team of about 25 patient-support, patient-access champions, and we sit within the larger commercial group at Xcenda. I think there's over 100 of us in the commercial consulting area. And we do everything from patient support programs, assistance, in terms of exposure modeling, and benchmarking, as well as policy work, coding, compendia, and reimbursement strategies—really the full gamut of working in addition to just your market access strategies.

To start us off, what do you see happening if the Affordable Care Act is struck down, especially with regard to the biosimilars approval pathway?

It is a tricky time right now, for a lot of different policies, given the Affordable Care Act and Supreme Court oral argument that we heard earlier in November. You know, when it comes to biosimilars, I'm not very worried, which is great, because there's enough things to worry about in 2020. And when it comes to biosimilars, yes, it is possible that it could be a little rocky for the biosimilars approval pathway, which is part of the Affordable Care Act. And one of the things that's in front of the Supreme Court right now is the question of whether it is severable? Is the whole law going away, or can they just separate parts of it that they disagree with? And so even if they somehow strike down the whole Affordable Care Act, which doesn't seem likely, given the way the arguments went, every interpretation is that it's a bipartisan agreement. Biosimilars are here to stay and the train has left the station. We have 28 approved biosimilars in the United States—18 that are on the market—and it would be pretty hard to stop it now. And, if the Affordable Care Act were to go away, I think we would have much larger problems than just for biosimilars.

Can you tell us about HR 8190 and what it means for the availability of affordable insulin?

Yes, 8190 is a bill that was introduced last summer in the House of Representatives. If passed, it would allow for biosimilar insulins to automatically be granted interchangeability designations. And you know what that means, simply put, is that right now, there’s no interchangeability. But this would enable pharmacists to substitute prescriptions, and switch patients to a biosimilar if their physician writes a prescription for the reference insulin, and assuming the biosimilar insulins are cheaper than the reference insulin, and we do expect them to be cheaper, patients would see immediate savings. And another benefit of this interchangeable designation is it would incentivize manufacturers to develop biosimilar insulin because they can be easily switched—leading to more competition and likely lower costs. And interchangeability could limit the investment in expense and time needed to introduce competition.

What do you think are its chances for passage?

When it comes to Congress, anything is possible. And, you know, I think that it's a clear benefit to patients with diabetes and should be able to generate bipartisan support. And the good news is it was introduced by Republican Grothman, a Republican from Wisconsin who did win reelection in November, so it still has its champion. That being said, Congress has many priorities, and I think this would need a larger bill—something else to kind of hitch a ride on to in order to get passed. But I think it does influence clearly a hot button issue and an area that a lot of patients would like to have some relief from, and so its chances are not necessarily good on its own. But the concept is one that I would expect to move forward soon.

Should this be accomplished by legislation? Or do you think the FDA ought to act to loosen interchangeability requirements?

We are waiting for the FDA to release guidance, potentially sometime next year, on the interchangeability requirements for insulins, but no one is sure what those requirements will be. Enacting this HR 8190 would secure the interchangeable status of biosimilar insulins and make it much more difficult to reverse the status in case the FDA doesn't move forward. Or, if they move forward and change their minds [on interchangeability, this bill would cement it anyway].

What can you tell us about insulin products that are under development and potentially approved as interchangeable?

Currently, there are no approved biosimilar insulins on the market. And we know that manufacturers are waiting for this guidance from the FDA to finalize their steps and move forward. And it's sort of a chicken and egg situation. You're waiting for something to happen before more happens, but I think that's where we're at right now.

And shifting to more health care policy questions, President Trump has sought to combat the high cost of prescription drugs, particularly biologics. How do you feel about international reference pricing, also known as “Most-Favored Nation”? And can you describe how this would work?

Well, I have very strong feelings about international reference drug pricing, the Most-Favored Nation, interim final rule that came out. I think it is important to recognize that the Most-Favored Nation Drug Pricing Rule that was released in mid-November really is about reimbursement and not pricing. And it is not the international price index that was released about 2 years ago; it's really about the lowest price on the market. And all of it starts less than 6 weeks from the day that HHS released the interim final rule.

They plan to completely upend the way that physicians are reimbursed for about 50 Medicare Part B drugs and biologics with high spending. The model is mandatory for physicians. It'll last 7 years, and all of it, you know, again in just a few weeks’ time, and I think that while this is really a huge change, I'm worried about it, and I don't like it. And I'm trying to figure out ways to make the best of this. I think it's important to note that there are going to be huge legal challenges in the next few weeks. We think that one of the main challenges that the interim final rule has is that the comment period is actually concluded after the rule has been implemented. So, if it's starting January 1, but the comment period was longer, how are you really implementing those comments? And so it was sort of, in some ways passed to fail. And we'll see what happens.

But just a little bit more about it, it's intended to lower the cost of select Part B drugs by mandating that the CMS pays no more than similar countries. And the model right now is set to be phased into full effect over 4 years. So, the first year will certainly not be as painful as it will be over time. And it's designed to test if removing incentives for high cost drug use in the United States will reduce both CMS and patient out-of-pocket spending without affecting the quality of care. Now, again, it starts with the 50 drugs; that cuts to the highest percentage of Part B expenditures, and more drugs will be looked at year over year. And what happens is, basically, you pay the lowest price available in those countries and it's looked at quarterly. CMS will look and say, “Well, this is the lowest price.” And you know, reimbursement for physicians for these drugs will no longer be based on average sales price plus 4.3%; instead, there's this new kind of Most-Favored Nation pricing, again phased in over 4 years, the model will allocate 25% of the reimbursement rate from average sales price to this Most-Favored Nation, and then it kind of phases in over time. Again, price can vary from quarter to quarter, and biologics are in there. And biosimilars are in there. And it's quite an achievement to get it out this quickly in terms of timing, but I think that it's an uphill battle for this particular piece of regulation.

How about importing high cost drugs from Canada? Is this really viable? And what about the risks of counterfeit drugs entering our health care system?

I think simple numbers tell the story when it comes to importation from Canada. Canada has 37.5 million people. The population of California is about 40 million. So, importing from Canda is not going to help the United States in the long run. I think it's a nice story to tell. I think that it is, you know, a nice political gimmick, but it's not going to be the answer to looking at drug pricing and reimbursement in this country.

What do you think is going to happen to these initiatives with the change in administration coming in?

If I can get a little geeky for a second, if Most-Favored Nation have been released as a notice of proposed rulemaking, I think that maybe President-Elect Biden could have done more with it, and made it and shaped it, and kind of done something to make it more tenable to himself and his constituents, as well as make it maybe more workable; but the way the Trump administration kind of rushed it through as an interim final rule, I think the legal challenges will stop it, slow it down, and ultimately, allow President-Elect Biden to stall it, get rid of it, and move it out. Which is, you know, somewhat unfortunate for him in that I think both him and President Trump have a similar kind of drug pricing mindset. So, there may have been more that the president-elect would have liked to have done with it. But for right now, I think it's just it's shelved. And for right now, President-Elect Joe Biden would have much more difficult things to worry about, probably than drug pricing, at least on day one.

And delving more into the transition to the Biden administration, what can you see in President-Elect Joe Biden's health care agenda that might improve biosimilar access and biologics affordability?

President-Elect Biden does certainly have a strong interest in making sure that drug pricing and drug utilization are efficient. And I think we've seen a lot of those trends over the last few years. And I think we're going to continue to see that pushing for the most efficient way of making sure that patient access is maintained. So, when it comes to CMS reimbursement or the FDA and interchangeability, none of those things, I think, will change. I think we're continuing on the path that we're on, which overall is a great thing.

Do you have any other thoughts on the Biden health care plan?

You know, the Biden administration has a lot of challenges. And I think the priority, of course, will be addressing the pandemic, I think we'll be looking at what happens with the Affordable Care Act, and, you know, coverage through the exchanges—whether he'll get a push from the left, more toward broader health coverage. All of these things, I think, in a lot of ways, are a larger challenge than drug pricing. Drug pricing, in and of itself, is a very newsworthy topic, but I think patient access is more important. And that's not necessarily tied to how much we spend on drugs. And I think that is a huge problem when it comes to Most-Favored Nation. And I think the focus on drug spending is inappropriate. I think, for the most part, you know, drug spending has gone up, and it should go up. We've gotten some fantastic innovation over the last 15 years. And we should be applauding that, and not necessarily saying, “Well, we're spending too much.” Maybe we're not spending enough. And I know as a consultant that that probably comes across as naive. But you know, we have fantastic innovation. We have people living longer. We have people being treated for things that we didn't have treatments for. And all of these are wonderful things; we have to make sure that as we look to solve problems, we're not creating new ones.

So, what do you perceive as some upcoming challenges to biosimilars in the coming year?

You know, the interchangeability issue, I think, is really important. And as we are waiting also for what's going to happen with the Supreme Court, there's certainly a lot of challenges. Also, when it comes to potentially Medicare Part D redesign, we're starting to move biosimilars into the Medicare Part D marketplace, which is really exciting, to finally be able to start talking about them in that context. We have a lot of manufacturers coming to us at Xcenda looking at how-to-do value propositions or how-to-do exposure models, or what does patient support look like? You know, what does market access look like? Can you help us with market strategies? We're also looking at coverage encoding for biosimilars. And all of these things are super challenging, and the next year is not going to diminish those challenges, particularly as the market gets much more competitive. As it moves to Medicare Part D, and you know, we've worked on every single commercialization for every single biosimilar in the marketplace so far. We're well-established and well-equipped to answer those questions, which is good because we've been busy doing so.

And concluding on a payer policy note, there's a lot of talk about rebates and how these and formulary decisions are harming provider choice on biosimilars and driving up costs. Do you see any movement here?

I don't think that rebates are necessarily the issue that is hurting patient provider choices to me; I think provider choice is really being harmed by step edits, by patient out-of-pocket spending, and yes, in part, those are rebate driven, you know, tools. But the rebate itself is not the problem, I think it's the payer response to the rebate that that worries me. Patient access, hindered by step therapy, hindered by out-of-pocket cost—that is really driving a wedge in that patient-provider relationship, which is so important. We've seen time and time again, particularly during this pandemic, how important it is and how much people do miss being able to go in and talk to their providers, and telehealth has been a great tool during this time. But I think you know, a lot of us are missing that one-to-one relationship. So ultimately, patient access being hindered by step therapy, and, you know, out-of-pocket is my main concern.

To learn more, visit our website at centerforbiosimilars.com. I’m Matthew Gavidia. Thanks for joining us.

We sat down with Jennifer Snow, MPH, vice president of Reimbursement and Policy Insights at Xcenda, to talk about health care reform efforts and how these would be affected by the change in administration. 