Tag: biosimilar news

Federal Policy and Biosimilars: A Conversation With Molly Burich, MS, Boehringer Ingelheim: Part 2

In part two and the conclusion of this interview, Molly Burich, MS, Director, Public Policy: Biosimilars and Pipeline, speaks to Boehringer Ingelheim’s progress in Cytelzo interchangeability studies, its plans for the product in Europe in the face of several adalimumab biosimilars launches in the EU, and also the complexity inherent in CMS’s plans to move biologic agents from part B to part D coverage.

Molly Burich, Boehringer Ingelheim
Molly Burich, MS

BR&R: Boehringer Ingelheim indicated that it started the study on Cytelzo interchangeability last year. What’s the progress on this effort?

Burich: The trial is continuing to progress. It’s a high bar and a big commitment. We will certainly publicize relevant information in due course.

We feel that for Cyltezo, in particular, interchangeability is an important component. It may drive switching. The study will also show a complement of clinical data around that topic. We hope to have information to share in the future. [Editor’s Note: The VOLTAIRE-X study, which will evaluate the effect of switching between Cyltezo and Humira in patients with plaque psoriasis, has an estimated primary study completion date of March 2020 and full study completion of July 2020, according to ClinicalTrials.gov]

BR&R: Speaking about Cyltezo, I have a question about the marketing floodgates being opened in the EU for adalimumab biosimilars. At least 4 are being launched in the EU after the October 16th patent expiration. Does Boehringer Ingelheim plan to join the fray?

Burich: Boehringer Ingelheim had planned to bring Cyltezo to patients in the EU. Due to the patent litigation with AbbVie in the US, we will not commercialize Cyltezo in the EU. Boehringer Ingelheim will continue all activities for our biosimilar in the United States. We are committed to making Cyltezo® available to U.S. patients as soon as possible and certainly before 2023.

PART B TO PART D TRANSITION BY CMS 

BR&R: Medicare has indicated that it will move many Medicare part B drugs into part D. To what extent will this affect biosimilar access and utilization?

Burich: It is a very hot topic these days. We have some pretty significant concerns on conceptually around what it means for moving from part B to part D. The key reason revolves around the access question, including patient cost sharing.

A move from part B to plan D could mean that patient cost sharing may jump significantly. We know that part B beneficiaries have wraparound or Medigap coverage to protect them from cost sharing issues. In part D, there is not such protection. Aside from the biosimilar question, the move from part B to part D really has to be explored and discussed a lot more to understand how we can ensure that patient access is not reduced through high cost sharing. That needs to be ironed out as it applies to any part B drug before we can speculate whether this is an opportunity for a biosimilar. Time will tell what that really looks like.

Last month, CMS released the Medicare Advantage guidance allowing for step therapy for part B drugs. That could be a potential opportunity for biosimilars, if we know how some of the access concerns will be addressed. We just don’t have the full picture at this point.

BR&R: Is it possible that this move to part D might spur some payers to create biosimilar tiers? These would require lower cost sharing for patients compared with reference biologics, assuming contracts with the reference manufacturer permits it.

Burich: In my opinion, we’ll need access to more biosimilars before we see a lot of that activity. It’s hard to foresee what big benefit design changes will be coming, but it’s certainly possible. We’ll need a mature market in the US before that will happen.

BR&R: The devil is in the details with this switching issue but there’s also an access issue. Plans can make midyear formulary changes, this would then apply to biosimilars and reference drugs covered under part D.

Burich: This is an important issue. The latest guidance that we saw from CMS, which is now a couple of years old, allowed positive formulary changes. Adding the biosimilar to a formulary is always allowed mid-year. The question involves removing an originator product or changing its tier.

CMS has said that those situations would be reviewed on a case-by-case basis. These rules preventing negative formulary changes midyear are there to protect patient access. It will take CMS some time to iron out what the process looks like for this type of potential formulary change midyear. For now, we’ll have to rely on CMS’s case-by-case review

BR&R: In general, payers do not consistently fund and manage self-injectable specialty drugs in the same way. In some cases, they cover these agents under the pharmacy benefits, medical benefit, or even both. Further, they can be managed under either benefit as well. However, it seems we are moving toward pharmacy management of these agents. How does this affect biosimilar access, if at all?

Burich: There will be more benefit design changes once we have a more robust biosimilar market. More specifically, when we have pharmacy benefit biosimilars.

We’ve mentioned CMS’s intention to move more of these products from part B to part D. It is possible that commercial plans will have different benefit designs and treat injectables differently than Medicare does. We want to make sure that biosimilar or not, the access piece is really at the center of those changes; it will not be beneficial to the biosimilar market if this move causes significant patient access issues (e.g., actual access to this drug or big swings in cost sharing). All of those things will be equally problematic for a biosimilar as they are for an originator, so we want to make sure we have our eye on the access component.

BR&R: Health and Human Services Secretary Azar and FDA Commissioner Gottlieb have loudly stated their desire to improve biosimilar patient and market access. The Biosimilar Action Plan was released earlier in the summer to that end. What is the one aspect of the Biosimilar Action Plan that appeals most to manufacturers like Boehringer Ingelheim?

Burich: The aspect of education, tackling both proactive education and countering misinformation is very critical from our perspective. We’d like to see more materials moving forward that focus on switching and on interchangeability. We haven’t really scratched the surface on those topics from an education standpoint.

The reality is that the FDA has an important voice and bringing validity to educational materials is so critical for patients, physicians, and health plans as well. We hope that the FDA will stand by its public commitment to release more reading materials, more videos, more web info, etc. It is especially important at this juncture; we are seeing misinformation and a lack of clarity on certain things.

IS THE BIOSIMILAR ACTION PLAN ACTIONABLE?

BR&R: One of the biggest barriers to biosimilar access is the patent thickets. The rebate trap problem is another story. What power does HHS have to clear out the patent thickets? Or is this an area that can only be addressed by Congress?

Burich: This is the most difficult part of the Action Plan, because it is unclear who can truly implement change and what change might be realistic. We have to protect true innovation that’s important to all stakeholders.

At the same time, there’s no question that patent litigation is the leading barrier to biosimilar accesss. Some makers of branded pharmaceuticals have constructed patent thickets so that they could sustain prolonged, expensive litigation against competitors, while stifling competition. Humira is the prime example: More than 15 years after the molecule was approved , no biosimilar is being marketed – in the U.S. What the answer is and which government agency can effect change has yet to be determined.

BR&R: That change won’t come quickly, in any case. Whether enacted by Congress or the Office of the Inspector General, which may have to reinterpret the safe harbor statutes, this may only first apply to the second-generation of biosimilar agents, beyond 2021 perhaps. It seems likely that this will be a very deliberate process.

Burich: I do believe Commissioner Gottlieb is thinking about both how to get more products launched in the short term and also the long-term vision of a sustainable biosimilar market. That is such an important part of the problem.

We were very happy that the FDA had their public hearing. The FDA panel asked a lot of thoughtful and probing questions to the individual speakers. We are fully supportive of the Action Plan and its individual components. If we saw all of those things come together and start to see action, including finalizing the interchangeability guidance and providing more education, the biosimilar market would be in a far better place.

BR&R: We say that biosimilar manufacturers can make their products attractive to payers, but payers need to play a positive role here. Commissioner Gottlieb has said that payers have to help in this process by taking the long-term view, by not automatically sticking with the reference product because of the rebate revenue. They have to be open to using the biosimilars and nurturing the health of the industry. Is there anything else the biosimilar manufacturer can do to convince payers to make this market viable?

Burich: Certainly, biosimilar manufacturers have to approach these payer negotiations and conversations with competitive and innovative contracting approaches. That does not just include pricing but also how do you drive volume and true savings to both payers and patients. That kind of innovative approach is necessary, because we know it’s a challenging market.

Biosimilar manufacturers have to look at the whole picture as well. That means providing targeted patient/physician services to really help ensure that the switching experience is seamless for the patient and the physician so that biosimilar utilization is not viewed as something very disruptive.

Word From the Adalimumab Front: A Conversation With Molly Burich, MS, Boehringer Ingelheim: Part 1

In the first portion of a two-part interview with Molly Burich, MS, Director, Public Policy: Biosimilars and Pipeline, Boehringer Ingelheim, we cover the challenges of driving biosimilar uptake, as well as the unique situation that has focused this manufacturer’s attention on biosimilars and interchangeability. 

BR&R: The viability of the US biosimilar industry is being challenged if companies cannot rely on revenue from switching, especially for the autoimmune category.

Molly Burich, Boehringer Ingelheim
Molly Burich, MS

Molly Burich: Yes, biosimilar uptake is certainly going to be dependent on switching. But switching comes in a few different types. One case involves patients who are going to be switched to a therapy with a different mechanism of action. Perhaps their existing therapy no longer works (or didn’t work in the first place).

Another case is medication substitution by the physician. The doctor drives that decision to switch the patient either to a biosimilar or to an interchangeable.

Lastly is automatic substitution, which will come as a result of interchangeability and enabled by state laws. However, that is only in play once a product gains the interchangeability designation.

All of those are important components, but certainly switching overall is an important part of the market viability.

BR&R: When we’re talking about automatic switching, multiple stakeholders are involved, including the prescribers, pharmacies, payers, patients. And none of it matters if we don’t have an interchangeable product or even final guidelines from the FDA on interchangeability. In retrospect, should we have made automatic switching for biosimilars based on something other than interchangeability?

Burich: There are a lot of stakeholders involved and this is. why multiple ways of switching will likely occur. In terms of switching, interchangeability allows pharmacists to switch one reference product prescription for an interchangeable one without intervention of the physician at the front end—pending state laws of course. The physician must be notified of the change.

In our opinion though, automatic switching is certainly not the only way to drive uptake of biosimilars. We believe physician-driven switching and payer-drive substitution via formulary decision-making are very important to drive the uptake of biosimilars.

BOEHRINGER INGELHEIM’S SINGULAR PRODUCT FOCUS

BR&R: Biosimilar utilization, and the overall market, has been growing slowly since the first biosimilar approval. Prospective biosimilar manufacturers have tended to jump into the market with both feet, filling their pipelines with multiple biosimilar agents. Boehringer Ingelheim may be the only major manufacturer with a single biosimilar listed on its pipeline web page. Is the company in a wait-and-see mode, to see if the industry will survive? Or is Boehringer making further investments in biosimilar development behind the scenes?

Burich: We are constantly in an evaluation process of our portfolio. Obviously, we are focused on our approved biosimilar Cyltezo® (adalimumab-adbm) and also on interchangeability, here in the U.S. That is our focus area. We believe that the introduction of biosimilars will improve the lives of patients, as well as contribute to the quality and economic sustainability of healthcare systems.

INTERCHANGEABILITY: MISUNDERSTOOD BUT NO SILVER BULLET

BR&R: The issues around interchangeability are particularly frustrating. At the time the BPCIA was written, was the concept of interchangeability (which does not exist in EMA regulations) an attempt to give prescribers and consumers a warm and fuzzy feeling of an AB-rated generic?

Burich: It’s an important question. As you said, when the BPCIA was written, interchangeability was viewed as a sort of silver bullet. The reality is that interchangeability is an important concept, but perhaps it makes more sense for only certain products. As we gain experience in the biosimilar market, we’re starting to see this.

We believe in the concept of interchangeability and in what the FDA has put forth about interchangeability. We do think there are questions about how an interchangeable product may be perceived compared with one that is not interchangeable. In our comments to the FDA, we encouraged the FDA to come out with educational materials that are geared toward talking about interchangeability, and talking about switching. These are all important questions and need to be addressed for the broad stakeholder community. The FDA is obviously best positioned to bring that type of education in the next round of materials they develop.

BR&R: We’ve heard a great deal about people mischaracterizing interchangeable products as being superior to biosimilars (for the same reference product). Why is this differentiation so important?

Burich: This issue speaks to education. All people engaging in the biosimilar space must realize that the designation of interchangeability does not mean it’s a higher-quality, safer, or more-efficacious product. It means that the manufacturer has conducted additional studies required by the FDA to enable that automatic substitution at the pharmacy level.

The FDA has issued clarifying pieces of information and education on their website about this, but there is room for more. The reality is that when a drug is approved as a biosimilar, it has attained the foundational designation proving that the drug is highly similar to the reference biologic, without any clinically meaningful differences. On the other hand, gaining the interchangeability designation is about conducting trials of multiple switches within the patient and expecting the same results in any given to patient. Those are two different distinctions. It proves something different, allowing for automatic substitution to occur.

In part two and the conclusion of this interview, which will be published in a separate post, Molly Burich speaks to Boehringer Ingelheim’s progress in Cytelzo’s interchangeability studies, its plans for the product in Europe in the face of several adalimumab biosimilars launches in the EU, and also the complexity inherent in CMS’s plans to move biologic agents from part B to part D coverage. 

An Update From BBCIC: A Conversation With Cate Lockhart, Program Director—Part 2

The Biologics and Biosimilars Collective Intelligence Consortium (BBCIC) is the organization that will perform the critical task of postmarketing surveillance for biosimilars and their reference biologics. Started in 2015, the BBCIC is a nonprofit, scientific public service initiative, which partners with multiple stakeholders to accomplish its mission. In the conclusion of our two-part interview with Cate Lockhart, PharmD, PhD, we explore how BBCIC is communicating with its stakeholders and whether the FDA’s four-letter suffix for biosimilars will assist in its tracking efforts. 

 

GETTING UP TO DATE WITH BBCIC ACTIVITIES

BR&R: Let’s talk a bit about what BBCIC is doing today. Can you give me an update on current BBCIC programs?

LOCKHART: Sure. We have completed our first round of descriptive analyses, composed of four studies that were designed to (1) characterize our patient population for these specific disease states and (2) understand our data. Can we reliably identify the cohorts of patients we’re interested in studying? Can we identify the outcomes that we’re interested in reliably? Do we trust our results, based on existing literature? What are the gaps in our capabilities? Those initial studies are completed, and we’re in the process of publishing those findings.

BBCIC Update
Cate Lockhart, PharmD, PhD

In the meantime, we have four work groups that are focused on methodological issues or filling in some of our data gaps. One group is working on best practices in comparative-effectiveness research (CER) methods. A lot of people are doing large-scale CER like this, but little consensus exists on best practices for performing it. We’ll come up with our own recommendations that will help guide our future research.

 

Another work group is specifically looking at switching patterns. The first phase of that work is completed. They identified methodological considerations for best approaching switching in the context of our research. We’ll soon be moving into the second phase, where we dig into BBCIC data and do a descriptive analysis, then we’ll start to understand the switching patterns in anti-inflammatory conditions, especially rheumatoid arthritis, and Crohn’s disease or ulcerative colitis.

BR&R: Will you be looking at switches from one biologic to another biologic? Or from one infliximab biosimilar to another? 

LOCKHART: Well, that’s a good question. With rheumatoid arthritis, patients may change therapies many times and with different types of treatments. So we’re really looking at any and all of those. We are starting to get enough utilization of infliximab biosimilar products that we’re hopeful that we can start to include them in the analysis.

BR&R: When might we read some published data on some real-world evidence with biosimilars? Will it be in early 2019?

LOCKHART: It will take a bit longer. As everyone in the US has experienced, biosimilar uptake and utilization has been slower than expected. As we discussed before, in order to do robust research in this space, where we are looking at relatively rare outcomes—whether it is safety or effectiveness outcomes—we need enough utilization numbers in order to start that research.

We are in the process of initiating our first CER study in G-CSF products, because we believe we do have enough biosimilar utilization in that category to begin.

We have one project that’s looking at NDC and J-codes to evaluate how physician offices are coding their utilization of and administration of both the biosimilar products and their reference biologics. We’re just in the data analysis phase of that, so we do expect to see some publications coming out of that in 2019. We will be presenting five posters at AMCP Nexus in late October.

BR&R: One of the missions of BBCIC is to be transparent about what it is doing. Please tell me about the communication efforts of the organization.

LOCKHART: One of major efforts this year is to get the word out about BBCIC; too few people are aware of the work being done.

Part of that is because during the first couple of years, BBCIC, which was officially convened in 2015, was very much in a start-up phase. The organization was just getting off the ground and running. My role is to begin the transition from start-up phase into one with much more of a public face.

We’ve moved beyond this start-up phase. We’ve finished research projects. We’re starting to publish based on these projects. Personally, I’m accepting any speaking opportunity I can. I’m encouraging BBCIC participants to go to meetings and present. We are starting to get a little bit more traction in that respect.

Another effort is our quarterly newsletter, which very cleverly is called the BBCIC Quarterly. I’m producing the newsletter as a vehicle to keep the broader community—and our current participants—apprised of where we are in our research, our progress, our plans, and where we are publishing or presenting results. That newsletter is posted on BBCIC.org. Anybody who is interested in receiving the newsletter can contact me, and I’ll add them to the distribution list. I’m getting good feedback on it as a way to just keep people updated on the general goings-on.

BR&R: The outreach is really needed. During the course of FDA Advisory Committee meetings or conferences encouraging public comment, I’ve heard many times the mantra “we need to track the outcomes of these biosimilars” or “are we going to be doing postmarketing surveillance?” This gives the impression that there are no efforts underway to do just that.

 

THE FDA’S SUFFIX: FOUR LETTERS OR A FOUR-LETTER WORD?

Yet, BBCIC is focused on postmarketing surveillance. Now, part of the ability to conduct studies of biosimilars and their reference biologics involves another highly debated issue: the four-letter suffix. What is your opinion? Do we need four-letter suffixes of biosimilars and their reference biologics to track them?

LOCKHART: I see the value on both sides of this polarized debate. We’re doing our NDC and J-code exercise to look at how these drugs are ordinarily coded and whether the suffix is used. The reality is, usage is quite variable today.

On one hand, I agree that putting a suffix just on the biosimilar does put up a flag in people’s minds that there is something different about this product. We don’t do that with generic drugs, but certainly that there is a very different context between generic drugs and biosimilars. But the philosophy behind biosimilars and generics is really not that different.

For tracking pBBCIC Updateurposes, there could be benefit in using the 4-letter suffix, but we can’t track it effectively if people are not using it for coding. And some of the coding systems being used today are not really designed to enter the suffix, so prescribers and administrative folks actually can’t code it in. There are some infrastructure challenges around that.

As much as I enjoy it when the government tells us to do things that are devoid of meaning, I personally believe that the use of random letters [in the suffix] makes it more confusing. I don’t remember what they are; the random suffixes are hard to remember, like –abda or -qbtx, with no meaningful context.

BR&R: At the recent AAM meeting, I heard Hillel Cohen from Sandoz say that of 69 adverse drug reports for filgrastim since 2015, all but four were filed without the four-letter suffix, and they were able to identify the correct brand, whether it was Zarxio®, Granix®, or Neupogen®.

It could be just as you said, that the administration system couldn’t handle the four-letter suffix, which is why it’s not entered. Or the providers ignored the four-letter suffix and used the INN and/or NDC code. Regardless, there doesn’t seem to be a rush to use the suffix in our early experience. Cate, from BBCIC’s perspective, is the suffix going to matter in terms of being able to track the use of a particular biosimilar?

LOCKHART: It’s really hard to predict. We’re in the position right now where infliximab is the only product where there’s more than one biosimilar on the market. If we’re looking at G-CSF agents, it’s not so complicated. It’s a hard question to answer, because it does rely so much on the infrastructure that we’re working with.

If we have these suffixes and nobody is using them, that’s missing the point. Some other countries don’t even bother with the suffixes—they just fill prescriptions with the brand name of the biosimilar. We still have a lot of inertia to overcome. Some of the controversy needs to be settled before we can even address the infrastructure problems.

From a BBCIC standpoint, I don’t think we know yet whether the use of the suffix will be critical, helpful, or neither. But, if providers or coders are not using the suffix in their claims, then it’s not helpful to us.

BR&R: Right. Well, it seems like pegfilgrastim may be the next test. We may have a second pegfilgrastim approval on or by November 3. That will mean two drug categories will have at least two biosimilars marketed. I’m guessing then it won’t be until into 2019 before we get a handle on who is using the four-letter suffixes for pegfilgrastim and who is not.

And the question of whether interchangeable products will get a unique identifier, no suffix, or something similar to the random four-letter suffix is still unanswered.

LOCKHART: That’s right. We still don’t know.

See Part 1 of our interview with Dr. Lockhart by clicking here. 

Fresenius Kabi and Celltrion Get Good News

A German manufacturer is considering its options after the successful completion of two clinical studies involving a pegfilgrastim biosimilar (MSB11455).

Fresenius Kabi, which completed its purchase of the biosimilar business from Merck KGaA in September 2017, announced its investigational biosimilar agent had proved sufficiently similar to the reference product Neulasta® in these phase 1 investigations (conducted in healthy participants). These may serve as pivotal investigations for the manufacturer, which said in its release, “Both studies are designed to enable the application for marketing authorization in the EU and US.” This may be the first indication that Fresenius Kabi seeks to be a player in the US.

Fresenius Kabi does not yet have an approved biosimilar on the European market. It hopes that MSB11455 may propel its fortunes on both sides of the Atlantic.

Food and Drug AdministrationIn its first study, the company reported that its biosimilar “met all primary pharmacokinetic endpoints, [maximum plasma concentration], and area under the curve, as well as the primary pharmacodynamic endpoints of absolute neutrophil count (ANC).” Fresenius Kabi added that there were no meaningful differences in the frequency of adverse events in these healthy volunteers. The second study focused on the biosimilar’s potential for immunogenicity, and this was also determined to be no different between the reference drug and the biosimilar. In addition, neutralizng antibodies were not found.

If Fresenius Kabi proceeds with an application for approval in either market, it will find a good deal of competition for pegfilgrastim biosimilars. In Europe, up to 5 biosimilars may be approved (2 already are). In the US, Mylan’s product is the only one to be approved, but another (Coherus Biosciences) is expecting a decision from the Food and Drug Administration (FDA) in early November. Two others (Sandoz and Apotex) are seeking US drug approval.

In other biosimilar news…The Food and Drug Administration’s Oncology Drug Advisory Committee voted unanimously (16-0) today to recommend Celltrion’s CT-P10 rituximab biosimilar for approval. If the biosimilar is approved by the FDA, it will be marketed by Teva….Mundipharma purchased European biosimilar maker Cinfa, which has a pegfilgrastim that has received a CHMP recommendation for approval in the EU.

An Update From BBCIC: A Conversation With Cate Lockhart, Program Director—Part 1

The Biologics and Biosimilars Collective Intelligence Consortium (BBCIC) is the organization that will perform the critical task of postmarketing surveillance for biosimilars and their reference biologics. Started in 2015, the BBCIC is a nonprofit, scientific public service initiative, which partners with multiple stakeholders to accomplish its mission. In the first post of our two-part interview with Cate Lockhart, PharmD, PhD, we explore how the organization is moving beyond start-up mode and towards providing real-world evidence on the efficacy and safety of biosimilars.

BR&R: Cate, what experiences or interests brought you to the BBCIC?

BBCIC Update
Cate Lockhart, PharmD, PhD

CATE LOCKHART, PHARMD, PHD: I was working in a small biotech company in Seattle. I was the health economics department. As is often the case in small biotech companies, it was a department of one.

I came into this role at the BBCIC in January 2018. Prior to that I’d been working on a part-time consultant basis with my predecessor, Bernadette Eichelberger, who was the architect of this organization. I had been working with her for a year and one-half or so, and to some extent, I learned about the inner workings of the BBCIC before I jumped into this role.

But what was really attractive to me was that it bridges a lot of areas of research, reflecting a lot of my experience in pharmaceutics, health economics, and pharmacy. This was, in so many ways, the perfect job for me because it really does marry all of those elements.

 

WHAT MAKES THE BBCIC TICK?

BR&R: Can you give us a little bit of a background on the collective intelligence methodology that underlies BBCIC.

LOCKHART: Sure. One of the unique elements of the BBCIC is our governance structure and the framework under which we operate. It’s a consortium, which means we bring together multiple stakeholders from a variety of perspectives. We have organizations who are manufacturers, we have managed care organizations, we have payers, we have some other nonprofit and some patient-engagement organizations. All of whom come to the table together for the common goal of conducting this research into the safety and effectiveness of biosimilars and their reference biologics.

Part of the logic behind that is, first, it helps to reduce some of the bias or perceived bias inherent in some research. Our work is not beholden to any one company, because all of the resources are pooled. In fact, some of our participating organizations are direct competitors, all sitting at the same table. That helps increase the credibility of the research.

Second, it gives us the opportunity to draw on the very broad expertise of our participants to hopefully make the research questions and the results that come out of our work relevant to as broad an audience as possible.

Third, it maintains a very high level of transparency. We operate under a charter. We have a board of managing directors. We also have a planning board or steering committee. Each of our participating organizations has a seat on the planning board. We have a science committee to help drive the scientific direction. We have a communications committee, and then we have our research teams. Each of these roles is clearly delineated in our charter, which is a publicly available document. We don’t operate in a black box.

BR&R: The BBCIC’s process is based on an existing program—the FDA’s Sentinel program.

LOCKHART: That’s a good point. The BBCIC is not part of the Sentinel program, but we leverage the infrastructure that was developed for Sentinel. The FDA spent a lot of time and money developing their common data model and coordinating its data partners to display and report their data in a specific way, so we’re leveraging that. There was no need to reinvent the wheel.

One key difference, in my opinion, is although our capabilities are very similar to Sentinel’s, our mission is a bit different. For one thing, we really are focused on biosimilars and their reference biologics. In that way, it fills a gap that FDA simply doesn’t have the bandwidth to address.

BBCIC UpdateThe research that BBCIC does is proactive. The FDA tends to be reactive, investigating potential safety signals once they occur. That is, they may receive a signal through their safety reporting system, at which time they can activate Sentinel and investigate the safety signal further. Their primary purview is response to safety.

On the other hand, BBCIC is proactively looking at safety and effectiveness in a real-world setting. That differentiates us to some extent from the other existing organizations that are doing this sort of large-scale, multi-stakeholder, multi-data source, observational research.

 

CAN WE CAPTURE SIGNALS OF WANING EFFECTIVENESS?

BR&R: Monitoring biosimilars’ efficacy or effectiveness seems to be extremely important, particularly with all of the discussions that we’ve heard about lot-to-lot variations and the potential for manufacturing changes. This also applies to the reference biologics.

Can you provide an example, if you can, of how the process might actually identify efficacy changes or maybe decreasing potency?

LOCKHART: We’re going into this under the assumption that there will be no discernible difference, because that’s what we believe. These products have gone through the FDA review process, and we trust the FDA reviewers and their process.

Effectiveness is a challenging outcome to measure when you’re analyzing administrative claims alone. So to get a better picture, we may be interested in looking at different types of data sources. Part of our work is to understand those gaps in data to measure effectiveness and identify other data sources that can help fill in the picture.

Because of the scale of our data “network,” for lack of a better word, we can more easily identify rare events. We expect the safety signals or signs of effectiveness changes to be [hiding] in the data, so you need to have a very broad, diverse network of data to identify those signals. With BBCIC, we have that breadth of administrative claims data to help answer some of those questions.

BBCIC Update

BR&R: When using an administrative data set, can we somehow identify switching as a marker for waning effectiveness? Hypothetically, if patients with rheumatoid arthritis who were receiving a biosimilar for etanercept began switching more frequently over time to a biosimilar or reference biologic for adalimumab, for instance, could that potentially hint at decreasing effectiveness? I’m guessing that one would need a tremendous amount of data collected from the various participating institutions to validate that sort of trend.

LOCKHART: It’s true. Switching is an interesting topic, and we’ve devoted a fair bit of time to it. When you’re starting to do observational research with administrative claims, adding switching into the mix introduces some difficulties in analysis.

You’re right—you do need a lot of data in order to really evaluate any switching trends, and you need enough longitudinal data in order to evaluate any outcomes. When a patient switches from one biologic to a non-biologic, from one biologic to another with a different mechanism of action, or between a biosimilar and reference product, you need to have data covering sufficient time of exposure in order to identify an emerging signal. We’re looking into some of those questions today.

It’s hard to answer the question of why a patient switched therapies. It could be a clearly administrative reason: A certain payer made a drug formulary change and suddenly covers only the biosimilar and not the reference product. That’s easier to identify. In some diseases, like rheumatoid arthritis, patients are on a pretty circuitous trajectory anyway, and they do a lot of switching. It’s hard to tease out what outcomes are a result of a switch versus a result of the underlying disease. Those are some of the difficult questions that we have to wrap our heads around.

We’re also looking into some methodological questions and developing some best practices for how to examine switching, because it does introduce quite a bit of complexity. That said, the European experience has yielded a richer field of data because of their longer utilization of biosimilars. Their studies have not shown, in the literature I’ve seen, any differences in safety or efficacy based upon switching. But again, teasing out the nuances is challenging with any data source.

 

Part 2 and the conclusion of our interview with Dr. Lockhart will be published in an upcoming post. 

Celltrion’s Rituximab Biosimilar Earns Positive Review

The information package released by reviewers for the Food and Drug Administration (FDA) indicates that a positive recommendation for Celltrion’s rituximab biosimilar is likely at the Advisory Committee meeting on October 10.

The members of the Oncologic Drugs Advisory Committee will review the data and hear public comments before voting to recommend that the FDA ultimately approve or reject CT-P10 for the treatment of non-Hodgkin lymphoma. Celltrion did not perform clinical trials for rituximab’s autoimmune indications. However, if the FDA approves CT-P10, it may extrapolate the approval to other indications as well.

The orirituximab biosimilarginal 351(k) application by Celltrion in April 2017 resulted in a complete response letter from the FDA. The rejection for this rituximab biosimilar cited multiple deficiencies, including “clinical, product quality, and facility” problems, as well as clinical study issues from the original submission.

According to the FDA reviewers, “In considering the totality of the evidence, the data submitted by [Celltrion] show that CT-P10 is highly similar to US-licensed Rituxan®, notwithstanding minor differences in clinically inactive compounds, and support a demonstration that there are no clinically meaningful differences between CT-P10 and US-licensed Rituxan in terms of safety, purity, and potency of the product.”

BR&R will cover the Oncology Drug Advisory Committee meeting and provide updates on its decision. If this rituximab biosimilar is eventually approved by the FDA, Teva would market the product in North America, based on a previous partnership agreement.

In other biosimilar news…Merck has inked an exclusive contract to supply its biosimilar infliximab (Renflexis®) with the US Department of Veterans Affairs. According to a report from Pharmaphorum, it will be the only infliximab biosimilar on the VA’s national formulary.

More From GRx+Biosims on Four-Letter Suffixes and Biosimilar Interchangeability

The talk at the GRx+Biosims 2018 meeting this month in Baltimore was about challenges, but extrapolation was not one of them. Biosimilar interchangeability was. That was not entirely surprising. In market research projects I’ve been involved with over the past year, payers and physicians in medical groups have broadly indicated that they’ve gotten past the extrapolation question. They are willing to accept the Food and Drug Administration’s (FDA’s) decisions on approval for indications for which clinical studies were not performed. In fact, some payers have noted a willingness to not discourage a biosimilar’s use for an indication for which the reference product was approved but the biosimilar was not. This, of course, assumes that it makes economic sense to do so. Many physicians still harbor concerns about switching therapy but not in treatment-naïve patients. In other words, if the payer prefers one product over another in a new patient, they would change their prescribing practices. In other words, they would not “rather fight than switch.”

Instead, the meeting, which was sponsored by the Association for Affordable Medicines and its Biosimilars Council, raised other questions, including the rationale behind the four-letter suffix and the complexities around biosimilar interchangeability.

Are Four-Letter Suffixes Needed?

Two greater questions were raised, one very practical and one theoretical one. The first involves the issue of the random (or sometimes not, as in -sndz) four-letter suffix, which is required for biosimilars in the US, but nowhere else in the world. Japan requires biosimilars to be designated with a standard “–bs” suffix. However, the European Medicines Agency does not utilize any suffixes and relies upon the international nonproprietary name (INN) for tracking purposes.

To make matters more complicated, the FDA intends to retroactively provide a suffix to all reference products as well, which no doubt will challenge billing and coding systems. The question is currently unanswered in the US as to whether interchangeable products will carry a unique suffix or share the same suffix as the reference product.

Hillel Cohen, PhD, Execubiosimilar interchangeabilitytive Director of Scientific Affairs for Sandoz, believes that these suffixes will not enhance the ability to track the use of biosimilars. Despite not using any special designations, “if you look at the European experience,” he said, “96% of safety reports have been made with proper attribution.” He pointed to the small database of biosimilar use accruing in the US. “Out of 65 safety reports registered so far, 62 came in with the brand name,” Dr. Cohen said. “None of the 65 reports were entered with the four-letter suffix.”

More on Biosimilar Interchangeability

Questions around biosimilar interchangeability still abound, partly because the FDA has not yet issued final guidelines around the approval process. Apart from the misconception that a product earning the FDA’s interchangeable stamp of approval is a “better” product than an ordinary biosimilar, two specific questions were explored, one of which is mind-boggling, the other merely frustrating.

The challenge extends from the expectation of lot-to-lot variation that occurs with biologic manufacturing. Assume that biosimilar A obtains FDA approval as an interchangeable medication, based on the switching studies against a reference product. As time passes, this manufacturing “drift” occurs. In a conversation with Dr. Cohen, he asked, “Is the biosimilar still interchangeable with the reference agent?” In other words, will the drug maker have to conduct more clinical switching studies to maintain this level of confidence, proving once again that the drug will provide equivalent outcomes in all patients compared with a reference product that is now also subtly different?

The second theoretical question arises from one I had discussed in an earlier post, the law of transitivity. If drug B is a biosimilar to infliximab, and drug C is approved as a biosimilar to infliximab, too, are drugs B and C biosimilars to each other? The answer, according to the FDA, would be no, because they have not be evaluated for physiochemical similarity to each other, only separately to the reference product. However, for payers, the answer is not so clear.

Dr. Cohen took that question one step further. If at some point in time, there are biosimilars A and D, both of which have been granted interchangeable status to adalimumab, are they interchangeable with each other? Again, the official answer would be no, because that is not how the testing was performed.

This brings up another intriguing question: if I’m living in a state that passed legislation allowing for automatic substitution of an interchangeable product, can a payer substitute interchangeable biosimilar A for interchangeable biosimilar D, if the former is the preferred product based on contracting? Technically, if the physician prescribed biosimilar D specifically, the pharmacy would not be able to substitute, without the doctor’s consent. The FDA has not designated biosimilars A and D as interchangeable for each other, only the reference product Humira®. The concept of biosimilar interchangeability is still, many years after passage of the BPCIA, an enigma.

Of course, based our situation in September 2018, this scenario is purely speculation, and will require multiple drug makers spending their R&D dollars to attain interchangeable status (to the same originator drug). That’s one reason why I like attending these conferences—they offer exposure to new, often confounding ideas!

Biosimilars and Drug Rebates: A Foot in the Door to Access?

At the September 5–7, 2018 GRx+Biosims meeting, I had the opportunity to moderate a session with three highly experienced biosimilar industry executives. They included Gary Deeb, Senior Vice President, Global Licensing and Business Development, Lupin Pharmaceuticals; Chrys Kokino, MBA, Head Global Biologics— Commercial, Mylan; and Mike Woolcock, MBA, Senior Vice President, Commercial Operations, Apobiologix. In the hour-long session, we covered a range of sticky topics. This post sums up some of the information gained on one aspect—the question of price transparency, recent FDA action to address drug rebates, and whether deemphasizing drug rebates will help biosimilars gain access.

One issue that is getting an awful lot of attention lately is the question of price transparency. This has been highlighted by the difficulties that Pfizer has had in gaining traction for its infliximab biosimilar, resulting in claims of exclusionary contracting by Janssen to protect the latter’s marketshare. One of the principal tools used by the reference biologic manufacturer is its power to rebate. When a drug has the lion’s share of utilization, rebates become very potent inducements to payers to provide or maintain preferred or exclusionary status on formulary. Therefore, the issue of biosimilars and reference drug rebates can be an important one for the industry.

biosimilars and rebatesIn response to the challenges of biosimilars gaining uptake in the US, Health and Human Services Secretary Alex Azar has been investigating whether safe harbor laws that currently protect drug rebates from anticompetitive lawsuits can be changed. This move can affect revenues for both pharmacy benefit managers (PBMs) and payers who share in the rebate monies. It raises a related question, however: Would biosimilar manufacturers be better off competing on list pricing (i.e., wholesale acquisition cost) alone? And does the issue of biosimlars and rebates really matter?

In the backstage green room, this topic generated much discussion among our panelists. And quite frankly, the answer to this question is not yet in.

In previous market research and access projects performed for pharma and their agencies, it has been clear that health plan medical directors and pharmacy directors would prefer competition based on discounted WAC, whereas PBMs prefer to retain their rebate revenue. However, the plans do share in drug rebate revenue to varying extents, which they are quick to point out are helpful in holding down premium increases or funding other projects beneficial to members and patient care. Hence, they are stuck in the rebate trap as well. They are not generally eager to add a new preferred drug even if the manufacturer is offering powerful discount WAC plus competitive rebate; they realize that the rebate revenue is based mostly on how much marketshare the drug maker can gain (and how quickly it can amass marketshare).

The biosimilar industry representatives at our panel discussion were similarly reticent. Does it represent an opportunity to break the exclusionary contracting hold of companies like Janssen? Without high rebates to cement a reference drug’s place as a preferred or the only covered biologic, other manufacturers can get their foot in the door and compete for marketshare based on price alone. This does not mean that prices would necessarily be more transparent, however. One would expect that discounted prices negotiated (from one plan to another or one PBM to another) would differ and remain confidential in nature. In other words, Kaiser Permanente Southern California could still only guess what Blue Shield of California was paying for infliximab and vice versa.

If the average sales price (ASP) methodology were unchanged, one would expect the ASP, which reflects discounts and rebates, to be closer to the WAC price by the amount no longer rebated. But the wild card in this scenario would be the pharmaceutical and PBM industries’ reaction. Is there a way to reclassify rebates as some other payment, like “administrative fees”? Our panelists believe that the PBMs, for example, will not easily forfeit a revenue line representing pure profit, regardless of its size. One would need to anticipate some attempt to retain this revenue.

The issue of biosimilars and drug rebates may only be shifted, in the end. Payers would still want to see the lowest net cost for any product. In 2018, they don’t care too greatly about how this is achieved, through rebates, discounts, portfolio contracts, or other means. If pharmaceutical rebates were deemphasized, my own guess is that at least biosimilar manufacturers would not be disadvantaged once approved, simply because they don’t have any existing marketshare. And it would also test a payer’s fortitude in foregoing its own drug rebate revenue.

Scaling the Mountains to Create a Biosimilar Market Success

One of the persistent themes at the Association for Accessible Medicines’ first GRx+Biosims meeting was an existential one. Authorities such as Gillian Woollett, PhD; Hillel Cohen, PhD; and several industry experts worried that without a change in mindset and intervention by government, payers, and the industry itself, the US biosimilar industry may not survive its infancy. And failure to attain US biosimilar market success would have grave consequences for the global biosimilars industry.

Biosimilar Market Success
Gillian Woollett

In her session, Avalere Health’s Senior Vice President Gillian Woollett, discussed the three mountains that biosimilar manufacturers had to climb in order to be successful. These were, in sequence, Mount FDA Approval, Mount Exclusivity and Intellectual Property, and Mount Commercialization. Indeed, it seems that FDA approval in many ways may be the easiest hill to summit.

Twelve biosimilars have been approved by FDA, but this is a far cry from attaining biosimilar market success. The eight drugs that are approved but have not yet reached the market are testament to this problem. Most have fallen victim to the lengthy delays associated with the exclusivity and intellectual property difficulties, none more so than the adalimumab biosimilars. For US biosimilar makers, each year that Humira® (and etanercept [Enbrel®] which will likely be introduced before 2020) face no market competition represents billions of dollars in unrecoverable revenue, as well as tens of billions of lost savings to the health system. Of course, it also means billions of additional revenues to the reference drug makers and their shareholders, which is substantially why these delays occur in the first place.

Don’t Look to the US, not Yet

Dr. Woollett asked, “Can there be a sustainable multisource specialty market in the US? I don’t think this is a foregone conclusion in the US.” She explained that the US is 50% of the market by dollar volume, yet it is home to only 5% of the world’s population. With aggressive tenders in many EU member countries, manufacturers are looking toward the US market to ensure long-term profitability. “Can the US carry the return on investment for biosimilars for the rest of world? I’m not convinced,” asserted Dr. Woollett.

Dr. Woollett pointed to another potential limiting factor in the commercialization of biosimilars. No interchangeable version of a biosimilar has yet been approved by FDA. However, switching matters greatly to the anti-inflammatory biosimilar drug maker, because it determines the size of the initial market opportunity. She explained, “If it applies to entire anti-TNF market, that’s $30.4 billion for infliximab. If you consider only treatment-naïve patients, that market is much, much smaller. If it is restricted to treatment-naïve patients, then no, these biosimilars will not be viable.” Switching is not a formidable issue for cancer biosimilars, as these are used as chronic treatments; nearly all patients are new to treatment.

She also noted a decline in the number of biosimilar development programs registered with FDA, which may be a signal of problems in the perception of manufacturers regarding their market opportunity.

Limited Reference Biologics Targeted
“Interest in biosimilar development only occurs for successful originator biologics,” Dr. Woollett pointed out. When filtering out biologics that are also not nearing patent expiration, it leaves a limited set of very expensive reference medications.

In making the business decision whether to develop a biosimilar, drug makers consider a number of questions, including the ease and cost of obtaining samples for evaluation, potential need for expensive clinical studies, and finally, what expense and time may be required for commercialization (including patent litigation). If a company plans on making the biosimilar available in a number of countries, it may be required to prove its molecule is adequately similar to samples obtained from each country or region. This could mean the need to purchase over 100 lots from the manufacturer, which is often not willing to sell to potential competitors. This is the reason for legislation like CREATES Act, which attempt to make this easier for potential biosimilar manufacturers.

Lowering Costs Through Harmonization of Comparators
However, Dr. Woollett and her colleagues in the biosimilars industry threw their support behind a different approach in 2017. Theirs is an initiative to establish “global reference comparators.” Under this approach, a manufacturer would only have to prove biosimilarity with a single licensed version of the reference product. “If the reference product is the same worldwide, then oughtn’t the biosimilar be able to be, too?” she asked. “Requirements for different datasets cannot be justified,” said Dr. Woollett. “Biologics been around for a very long time.

Biosimilar Market Success
Hillel Cohen

Once approved, complexity is no longer a relevant argument.” This would eliminate the need for biosimilar makers to confirm equivalence in bridging studies between their molecule and the licensed standard approved by each jurisdiction.

This approach reflects a growing understanding that the lot-to-lot variations seen in usual manufacturing of biologics (and over time) do not generally represent a risk to patients in terms of clinical effectiveness or safety. This, Hillel Cohen, PhD, Executive Director, Scientific Affairs, Sandoz, has just not shown to be an issue over 20-odd years of biologic production (outside of the Eprex® incident in 1998). In essence, today’s biologics are biosimilars to the original product approved by the FDA or EMA decades ago, without adverse effect on efficacy or safety. He pointed out that bridging studies that have been required add time and complexity to biosimilar development. Global comparators would help resolve this, and it can be applied to both biosimilarity and interchangeability comparisons as well. Dr. Cohen noted that “the FDA’s draft interchangeability guidelines still require comparison with US-licensed reference products only.”

Interchangeability not a Guarantee of Biosimilar Market Success 

Dr. Cohen said that when a biosimilar product is so extensively studied as to its comparability with the reference product, “I cannot imagine scientifically why we thought switching would be a problem. In the opinion of the EU, these agents are substitutable, under proper supervision, with clinical monitoring. Indeed, the concept of interchangeability is unique to US regulations. However, even this designation may not hold the key to biosimilar market success.

Leah Christl, PhD, FDA, agrees with EMA that biosimilars in theory are interchangeable with their reference for the purpose of MD prescribing (meaning they are substitutable). This helps address the question of whether a noninterchangeable biosimilar is somehow a lower quality or less equivalent to a reference product than an interchangeable biosimilar might be. In fact, Dr. Cohen pointed out, “There is no definition of a ‘noninterchangeable biosimilar’ in the BPCIA.”

The cost of development of biosimilars, which may be in the hundreds of millions of dollars, is very high, considering that only four have been launched in the US. Dr. Woollett thinks that something will have to change in order for biosimilar manufacturers to maintain their interest in this sector. Yet, in view of the limited options available in the US to remedy the situation, Dr. Woollett remains pessimistic. “These investments in biosimlars of up to $500 million will be reconsidered,” she concluded.

At the GRx+Biosims meeting, Secretary Azar’s assistant Daniel Best restated the administration’s desire to preserve the biosimilar industry for the benefit of lowering prices and greater competition. He said, “We absolutely have to find a market for biosimilars. We can’t allow it be be eradicated through the perverse incentives in the marketplace.”

In fact, the only biosimilar market success story to date, Zarxio®, may be as much the result of a certain set of preconditions as that of Sandoz’s marketing efforts. First, another branded product, tbo-filgrastim (Granix®), was already available and was eroding the share of Amgen’s reference product. Second, this agent, though not technically a biosimilar by the regulatory approval pathway, cleared away some of the patent issues for Sandoz in its development of Zarxio. Third, Amgen eventually yielded the top position to Sandoz (at around 40% of marketshare). This set of circumstances is a bit unlikely for the introduction of other biosimilar drugs. Many will be looking to Mylan and its commercialization of pegfilgrastim as the next test of biosimilar market success.

FDA Purple Book: Much Potential Value, Little Current Help

Under the BPCIA, the FDA Purple Book is the published agency reference on biosimilars. It lists very specific information with regard to both the reference biologics and biosimilars: (1) biologic licensing application number, (2) nonproprietary name, (3) proprietary name (brand name), (4) date of licensure, (4) reference product exclusivity expiration, and (5) whether the product is a biosimilar or interchangeable product.

FDA Purple BookHowever, the number of patents existing on a specific reference product and the complex nature of the web of exclusivities, has compelled several speakers at a September 4, 2018 public hearing on biosimilars to question the value of the current Purple Book information.

FDA Purple Book
Mariana Socal

At the FDA-sponsored hearing, Mariana Socal, MD, PhD, MS, MPP, from the Johns Hopkins Bloomberg School of Public Health, stated that the FDA Purple Book should focus more on competition, “providing both proprietary and nonproprietary information.” She believes that “the drug identification information should be expanded,” to include administration, dosage form, strength, pediatric use, and orphan drug status. She would rather the FDA Purple Book publish much more information regarding the active ingredient, “and all unexpired exclusivity periods should be published in the Purple Book.” For those patents found to be eliglible, the 12-year reference exclusivity under BPCIA should be determined and published definitively in the Purple Book.

“The Purple Book should include information on all unexpired patents that the reference manufacturers reasonably believe protects their biologic product,” said Dr. Socal. Otherwise, it forces prospective biosimilar drug makers to sift through hundreds of complex pharmaceutical patents, “making it easy to miss a key patent.”

“The FDA is authorized to do this under the Public Health Service Act,” she stated. Increasing transparency and reducing uncertainty are building blocks of the effort to improve timeliness of access to biosimilars.

According to Dr. Socal and other speakers like Michelle Cope at the National Association of Chain Drug Stores and Christine Simmon at The Biosimilar Council, the implication is that the FDA Purple Book needs to be more of an assistive tool to improving access to biosimilars rather than simply a reference on what has been approved.