A More Useful Way of Evaluating New FDA Biosimilar Applications

A Conversation With Gillian Woollett, MA, DPhil, Senior Vice President, Avalere Health

In the conclusion of a two-part conversation with one of the real go-to experts in the biosimilar field and US regulatory process, we talk with Dr. Woollett about the need for a new approach by the FDA when evaluating biosimilar applications.

Biosimilars Review and Report: Gillian, you and your colleagues have been advocating the FDA to move away from its “totality of evidence” approach in its decision making on new biosimilar applications. You’ve dubbed your approach “confirmation of sufficient likeness” (CSL).

Gillian Woollett, MA, DPhil: We believe that it’s much closer to how we should be evaluating biosimilars going forward and capitalizes on the experience gained to date in the highly regulated markets. We have to be more efficient in the interests of patients and their access to critical biologics, including biosimilars. And our approach means no reduction in the quality, safety, or efficacy of the biologics approved.

Gillian Woollett

BR&R: What are the main differences between your new paradigm and the FDA’s totality of evidence approach?

Woollett: There is a semantic difference, but it’s also conceptual. And to be fair to the FDA, it’s what they’ve actually been doing in some cases already.

The current approach presupposes residual uncertainty in a manner that we don’t apply to comparability in support of manufacturing changes for currently approved biologics. This leads to the presumption that what you don’t know for a biosimilar makes it different from the reference product. We tried to turn it around, which is to say that you’re manufacturing a drug that you expect to be essentially the same. By so doing, you are actually building up your confidence, hence confirmation, of sufficient likeness. As you complete each step in biosimilar development, you’re confirming that the target product profile is actually what you expect it to be and the drug performs the way you expect it to do. The same molecule inevitably behaves the same way. That is the premise of comparability that is now being applied, as a regulatory scientific matter, to enable biosimilars. After all, the only difference is a different sponsor. Bottom line: The science is the same, so let’s use it better in regulatory practice.


Woollett: In our paper, we evaluated what actually happened in Europe, US, Australia, and Canada. We reviewed the outcomes of all those biosimilar applications, finding a very clear pattern that if a biosimilar candidate’s pharmacokinetic (PK) data matches the reference product, the product will be approved. This leads to next question: Haven’t we already confirmed at that point the drug is sufficiently similar? What do we learn from subsequent clinical studies?

While we reached a conclusion that may be controversial, it is scientifically rock-solid, and no one has challenged our reasoning. Given that any additional clinical studies are less sensitive than the PK analysis, you actually know what the outcome will be. Therefore, additional clinical studies lack scientific validity, and this means, inevitably, that they also lack ethical validity. They are telling you nothing new and as such cannot comply with the Declaration of Helsinki.

Now while some may not be keen on this conclusion, no one has repudiated it scientifically. Efforts to date appear to dismiss the value of the PK study, even as European regulators have independently reached the same conclusion we have using a different data set.

BR&R: Well, the FDA itself has started moving away from the confirmatory studies, the large phase II and phase III evaluations.

Woollett: It’s a mixed bag. I think it was at the FDA Advisory Committee meeting for the first adalimumab biosimilar, the FDA said that the sponsor did an extra study that was not requested. The study involved a second indication, and the sponsor did the study of their own volition, for marketing purposes. Sadly, that is seen as necessary, because of the lack of understanding by physicians, but it is a very cynical response.

Part of the reason we came out with this paper is to say that expecting these additional studies has massive consequences. Quite apart from being unethical (which should be reason enough not to do them), they are expensive, they take a lot of time, and they are barriers to entry for the smaller companies that can’t afford investments of this magnitude, and they don’t result in better biosimilars. These large clinical studies are essentially meaningless, and they come at a price for competition and patient access.

BR&R: On a gut level, it seems reasonable to apply this approach to drug categories that have already been reviewed by the FDA. Can you easily use this CSL approach in biosimilars for new reference drug classes, like ustekinumab or aflibercept?

Woollett: There’s no need to rely on guts. Let’s stick to scientific fundamentals—you do a study because it is going to tell you something. If you’ve established that the PK studies have demonstrated a good match with the reference product, what should that next study test? On what scale? Are we reverting to a full, phase III? We always used to call them confirmatory—not phase III—studies. What is it confirming, if you don’t have a statistically meaningful sample size to demonstrate outcome differences? At the moment these additional studies fall between two stools—and that simply won’t do.

Another interesting consideration is the situation in which a great deal of real-world evidence (RWE) from Europe or other highly regulated markets exists, with good documentation of adverse events matching those of the reference. This should also be considered confirmatory, because it is actually a postmarketing study of real-world use, demonstrating that the product is behaving in the expected manner.

That can come with risks for the originator, too. For example, the trastuzumab issue that has been in the news: The structure of the originator (Herceptin®) has varied sufficiently through glycosylation changes to apparently alter its immunological properties. Biosimilars that were produced to be comparable to the original version of Herceptin did not match in PK to other later versions of the reference. The glycosylation changes also led to clinical differences. This has been documented in the peer-reviewed literature.1-4

BR&R: That version of the originator trastuzumab was not even “biosimilar” to the original reference product?

Woollett: Apparently, the original sponsor has now changed back to a version that more closely matches the earlier version of their own product. There were seemingly clinical consequences in terms of reduced efficacy, so the reason for biosimilar’s failure of the PK testing was that it was more effective than the altered reference, as in the biosimilar was actually as effective as the original Herceptin. My understanding is that the reference is now back to where it was, and that the PKs of the biosimilars match. 

When its sponsor wanted to produce a more concentrated version of Humira® that does not contain citrate, the FDA noted that this new version failed a PK comparison with the original version. It was approved. It didn’t fail by very much, according to the FDA’s review, but it is still arguably a lesser standard than we expect of biosimilars. I don’t know if it’s clinically meaningful for adalimumab, but studies showed the changes to be clinically meaningful for trastuzumab. Hence, I’m reaching the point of saying, “We’ve seriously got to consider the use of PK in comparability.” And that may be even more heretical than our ideas on biosimilars—but we must be consistent, and we must use sound science as the basis for all our regulatory decisions. My drumbeat is consistency, consistency, consistency.

And that then brings us back to CSL: you should never do any study, let alone a clinical study, if the result doesn’t tell you something. But in all cases, with all biologics, you had better do the studies that tell you most—and that may indeed be PK. Indeed the European regulators have termed it the “gatekeeper assay.” That might just be right even more broadly.


BR&R: From an economic perspective, changing to the CSL approach could save prospective biosimilar manufacturers millions of dollars.

Woollett: That is likely true, but the science demands it, as do requirements for ethical clinical studies.

It’s not just the money, it’s also time and that may enable more, as well as potentially even more cost-effective, biologics available to patients sooner, too.

BR&R: Has anyone analyzed the potential time savings in bringing a biosimilar product to market using the CSL approach?

Woollett: We didn’t do that, but the numbers could become really interesting if we combined it with the use of a global reference. At that point, we are beginning to approach the concept of a global dossier. This is what we expect today for originator biologics—as we should. But the same should apply to biosimilars to those originators, surely. Again, our real theme here is consistency.

Meanwhile we do support the regulators continuing to be agnostic as to the business model of any sponsor. We are also suggesting that they should be efficient with every product; reassuring or “feel good” studies really won’t do. Indeed, I believe the biggest opportunity for the regulatory efficiency we advocate is with originator products, worldwide of course.


BR&R: Well, that’s a perfect segue to a discussion about global comparators. We alluded earlier to the two versions of the reference product licensed separately in the EU and US. These two molecules were approved using essentially the same investigational data. To an extent, the EU and US originator versions are expected to be “biosimilar” to each other. This is not proven unless “bridging studies” are performed, comparing these reference licensed versions head to head. Yet no one argues that an originator agent in the US is associated with different outcomes than the one used in the EU.

It seems to be pointless today to require the bridging studies between the two. How do you position and select the global comparator?

Woollett: There is never an expectation of clinical differences within a single BLA. As such anything that the regulators have accepted within a single application is still contributing to one set of “goalposts.” The, fortunately extremely rare, comparability failures, including Eprex® (epoetin alfa) in the early 2000s, the trastuzumab issue, and the different adalimumab versions we just discussed, are not an indictment of the power of analytics plus PK. They are just examples where the approach wasn’t followed for the originator products and where we may need to be more careful in the future.

Just like with Rituxan® in Schiestl’s 2011 paper, a change in glycosylation for Herceptin® led to a change in antibody-dependent cellular cytotoxicity (ADCC).1–4 This is an omission in the use of analytics to establish high similarity, not evidence against the use of analytics as the primary basis for comparability and biosimilarity.

The single biggest message I have on all of this is that biosimilars cannot succeed until we are clearer about how much the originators have varied. It is the originators that have broadened the “goalposts” that the biosimilars must target. And that is, in the vast majority of cases, perfectly OK.

Many physicians and their patients appear to think the originator is cast in stone. But all biologics are essentially “biosimilars” to themselves as a scientific matter. Some stakeholders are not comfortable with that message being out there, and yet it is a good one for the continued use of comparability. That is what was meant in Schiestl’s brilliant title: “Acceptable Quality Variation in Approved Biologics.” This variation is acceptable and is carefully overseen by regulators—and has been since 1996 when FDA led the world with the concept.

BR&R: One more practical aspect on the use of a global comparator: Would it be a hell of a lot easier for prospective manufacturers to get samples for the product?

Woollett: In all likelihood yes, and make it more affordable, because the US versions are usually the most expensive. But that is not the biggest reason. By far the most important reason is that it is scientifically and ethically right to minimize unnecessary clinical studies, and to be efficient in the development of all medicines, always. Science-based regulators have to want that too, as do all other stakeholders. Let’s get there together.


1. Pivot X, Bondarenko I, Nowecki Z, et al. Phase III, randomized, double-blind study comparing the efficacy, safety, and immunogenicity of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients with neoadjuvant therapy for human epidermal growth factor receptor 2–positive early breast cancer. J Clin Oncol. 2018;36:968-974.
2. Lee JH, Paek K, Moon JH, Ham S, Song J, Kim S. Biological characterization of SB3, a trastuzumab biosimilar, and the influence of changes in reference product characteristics on the similarity assessmentBioDrugs[published online, June 12, 2019].
3. Pivot X, Pegram MD, Cortes J, et al. Evaluation of survival by ADCC status: Subgroup analysis of SB3 (Trastuzumab Biosimilar) and reference trastuzumab in patients with HER2-positive early breast cancer at three-year follow-up. Presented at American Society of Clinical Oncology Annual Meeting 2019; May 31-June 4, 2019; Chicago, IL. Abstract 580.
4. Pivot X, Pegram M, Cortes J, et al. Three-year follow-up from a phase 3 study of SB3 (a trastuzumab biosimilar) versus reference trastuzumab in the neoadjuvant setting for human epidermal growth factor receptor 2–positive breast cancer. Eur J Cancer. 2019;120:1-9.

Insulin Transitions: A Dead Zone in the Gap Year, and Other Considerations

An Assessment With Gillian Woollett, MA, DPhil, Senior Vice President, Avalere Health

In this two-part conversation with one of the real go-to experts in the biosimilar field and US regulatory process, we talk with Dr. Woollett about the upcoming transition for insulins and other pharmaceuticals in March 2020, when they become regulated as 351(k) biosimilars.

BR&R: Partners Mylan and Biocon recently received a second rejection for its insulin glargine follow-on product, because of the FDA’s inspection results of Biocon’s production facility in India. If they do not get approval by the FDA by March 2020, will they have to submit a new 351(k) biologic licensing agreement (BLA)?

Gillian Woollett, DPhil, MA: In all likelihood yes, but they can’t submit a BLA yet, because there is no reference product for comparison. I’ve been calling this period before March 23, 2020 the “dead zone” and after the “gap year.”

Gillian Woollett

BR&R: Is it possible, since we’re not talking about clinical deficiencies in the product’s data, that some sort of appeal process can be implemented to spare Mylan and Biocon from having to start the BLA process from scratch?

Woollett: We should not presuppose the nature of the deficiencies as any complete response letter is confidential to the sponsor. If the FDA’s concerns are answered by this coming March, there may be no delay. However, after is more of a challenge.

Even if a sponsor is able to submit a BLA on March 24, 2020, it will likely take FDA at least another year to review the application (the “gap year”). Most of the physiochemical and clinical data can be expected to be the same, at least, but this is still a lot of extra work. We likely won’t have an interchangeable insulin until the end of 2021 at the earliest. Hence, as outlined in our paper, this transitional process for insulin will delay competition, not enhance it. And that is a pity for a product as fully characterized as insulin, where we need competition to enhance access.

BR&R: Based on an analysis we did back in June, very few manufacturers have publicly disclosed an interest in producing a biosimilar insulin at the moment. Do you think prospective manufacturers have been discouraged by the transitional timeline?

Woollett: Even in Europe, I think they’ve struggled a bit. Maybe that’s related to the nature of the reimbursement in Europe.

If they are part of the “prequalification” for biologics being undertaken at the World Health Organization (WHO), many other things should be considered in getting global access to your insulin. The WHO’s prequalification effort, albeit limited to date to a pilot for rituximab and trastuzumab, may be particularly helpful to countries with limited drug regulatory capacity. My understanding is that insulins have not been added to the list, as a regulatory matter, but are being considered.

Under this prequalification, if a biosimilar (or other drug) was approved by an agency in a highly regulated market, then that product can go on the list. However, for inclusion on the WHO’s list, the drug also has to be launched—not simply approved. This was addressed specifically in March at the Medicines for Europe meeting in Amsterdam as a problem for biosimilars. The WHO is applying a hurdle over and above FDA approval, which strikes me as a little unnecessary and somewhat counterproductive.

Some companies have extensive experience with their insulin products, but it is not documented in the manner of the highly regulated markets. We hear a lot about real-world evidence in the US, but it is not really being accepted yet.

This is another area I believe the WHO should be going—setting the ceiling as well as the floor, because what we tend to do in the highly regulated markets is overdesign things. We tend to measure parameters, simply because we can (regardless of whether they matter clinically). I call it the “EPA problem”: You only have a contaminant in the environment when you can measure it.


BR&R: Let’s talk about another instance of overdesign in our market, with insulin nomenclature and the transitional process.

Woollett: The FDA has indicated that they will not give these transitional products suffixes to their nonproprietary names. This is super important: The Agency apparently realized just how problematic and expensive changing the nonproprietary names to currently marketed products was going to be, and that they were being tracked adequately today. It would be a challenge to switch every database at midnight, throughout the supply chain, on the date of the transition to include the four-letter suffixes. This is a good decision and huge relief to many stakeholders.

The original draft guidance on nonproprietary names had the suffixes apply to approved biologics and biosimilars. The Federal Trade Commission (FTC) had made the case that having a suffix only for biosimilars flagged them as different, and anything that differentiates is necessarily a problem for competitiveness. This is what I call “friction” in the marketplace and will deter switches between reference and biosimilar products. By being fair, the suffix had to apply to all biologics, which raised the problem with the transitional products.

The databanks flagged the problem as a practical matter and massively expensive to reconcile. So, the FDA decided that drugs rolling over to the biosimilars would not receive suffixes. This will apply to all the transitional drugs—hyaluronidases, hormones, insulins, and somatropins, etc. All new products in these categories will get suffixes, irrespective of biosimilar or originator status. So “new” insulins, whether originator or biosimilar, will get suffixes, and this is going to be inordinately confusing, too, but not as expensive to implement.

Insulin biosimilars

BR&R: If they don’t apply a suffix to Basaglar®, for instance, and they do so for any transitional product approved after March 2020, it still undercuts the purpose of having the suffix—for identification of individual drugs.

Woollett: Agreed. It is evidence that you don’t need the suffixes in the first place. My overall objection to all of this is inconsistency. If you have a reason to do it, you’ve got to do whatever it is you’re doing for all products… and that is not what is happening.


BR&R: Well, consistency has not been the FDA’s strong suit. And that goes for the interchangeability of insulins as well.

Woollett: Further, none of the products rolling over can ever be designated interchangeable, because they are not biosimilar in the first place, not even Basaglar.

BR&R: Exactly! Here’s the inevitable problem where the rubber meets the road: You’re a patient at a health plan. You have been receiving Lilly’s Humalog® to control your elevated blood glucose levels. Unfortunately, you need to switch health plans next year, and the new plan doesn’t cover Humalog. It covers Novolog® and excludes Humalog or offers it at a nonpreferred copayment tier. The health plan is not interested in whether these two insulin products are interchangeable from a regulatory standpoint. The same is true with the infliximabs and filgrastims.

Woollett: It has always been true that formularies change, but it is still the physician who is doing the prescribing, and so that is OK. For interchangeability, we are only talking about someone other than the original prescriber making the switch.

And by the way, for a biosimilars, it’s not that you are not interchangeable, it’s that you are not yet designated as interchangeable. People are saying that biosimilars are “not interchangeable,” but there’s no such thing. There’s only “designated as interchangeable.” The labels of all the currently approved biosimilars are silent on interchangeability.

BR&R: From a coverage or health plan standpoint, it doesn’t really matter to them.

Woollett: At the plan level, no. Presumably, the plan would just say, “Basaglar® is covered” and simply that there’s no coverage for Lantus®, the reference product for Basaglar®. Today, Basaglar® could be designated as therapeutically equivalent with no extra clinical studies. But after the rollover, Basaglar can never, ever be designated an interchangeable product that the pharmacist can automatically substitute, which seems crazy.

BR&R: Right. Something else that you’ve pointed out in many of your pieces is the problem that these products—outside of being delivered via syringe and needle—they almost always have unique pen-delivery systems. They are a combination of device and product. If you approve these combination products through the 351(k) pathway, will the FDA then have to consider the delivery device in the determination of biosimilarity?

Woollett: That was addressed, if you remember, with the first guidance on interchangeability. The Federal Register notice had two questions outside the draft guidance itself, and one was about human factors and included the devices and self-administration questions. The FDA apparently decided to keep those outside the interchangeability guidance itself, and that was wise. Nonetheless, many of the insulins are essentially combination products.

In part 2 of this interview with Dr. Woollett, we discuss her call for the FDA to move away from totality of evidence, and to “confirmation of sufficient likeness” in its evaluation of biosimilar BLAs.

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.

Plans Use Step Therapy to Encourage Utilization of Remicade Over Biosimilars

Health plans and insurers are not yet turning to biosimilar infliximab as a preferred therapy, according to Gillian Woollett, DPhil, MA, of Avalere. Her new report surveyed publicly available policy about health plans across the nation. The principal finding was that step therapy was commonly used  to encourage use of the originator product.

In fact, just one health plan (representing 1% of the 172 million lives covered in this study) supported the use of either Inflectra® or Renflexis® over the reference product Remicade® through step therapy. One plan (2% of the covered lives) allowed the use of either the originator product or Inflectra as a first step.

Gillian Woollett of Avalere on step therapy and biosimilars
Gillian Woollett

Four of the 18 plans with publicly available information did not utilize step-therapy rules for any forms of infliximab. However, “10 of the 18 plans (55% of plans, 52% of covered lives) require the use of [Remicade] first, alone or in combination with another DMARD,” stated Dr. Woollett in the report. A total of 81% of the covered lives from these 18 plans were subject to step therapies limiting access to one infliximab product or the other.

On its face, this type of step policy makes a bit of sense. Step therapies are often used alone or part of prior authorization mechanisms to make sure patients try more cost-effective agents first. In rheumatoid arthritis, that may comprise use of nonbiologic drugs before proceeding to a TNF inhibitor and then to another biologic in patients with rheumatoid arthritis. However, there is no proven benefit (or even logic) to offering a biosimilar infliximab after failing Remicade, or vice versa. If there was a significant clinically relevant difference in immunogenicity, this could be an issue, but this also has not been seen in practice. It makes more sense to try another anti-TNF or perhaps even move to an interleukin inhibitor—something with a different (or slightly different) mode of action.

A policy such as this can confuse the issue for patients, whose knowledge of biosimilars seems tenuous, and even providers, some of whom have little experience prescribing them, particularly because of payers’ Remicade-first policies.

The Avalere report provides some support for how payers are arresting utilization of biosimilar infliximab in favor of the originator infliximab product.

Dr. Woollett paints a very different picture for subcutaneously administered filgrastim products. Forty-nine percent of the covered lives (five large plans) had policies favoring Zarxio®, whereas 27% of covered lives were encouraged to use Neupogen® first.  For these 18 plans, five (28% of plans, 49% of covered lives) demonstrate a preference for the biosimilar, filgrastim-sndz. Five (28% of plans, 27% of covered lives) demonstrate a preference for the reference filgrastim. Eight plans (44% of plans, 24% of covered lives) do not indicate a preference through formulary design. A further 24% were not subject to any preference.