Tag: Hillel Cohen

Biosimilar-to-Biosimilar Switching: The Data Say Its Fine

The question of interchangeability for biosimilars has haunted the US Food and Drug Administration since the promulgation of the Biologics Price Competition and Innovation Act of 2010. The FDA’s draft guidelines on interchangeability evolved very slowly, and the biosimilar industry had to work to (1) keep up with the guidelines as they gained clarity, (2) tirelessly wage war on misinformation as to what an interchangeable biosimilar actually represented, and (3) grasp the value of interchangeability as a for-profit enterprise and whether to charge forward with the necessary clinical trials.

In this column, we have often addressed the interchangeability designation, and how it may be perceived. Leaders in the industry, like Hillel P. Cohen, PhD, Executive Director, Scientific Affairs, Sandoz, have hammered home strong arguments that interchangeable biosimilars are not “better drugs” than their noninterchangeable brethren. They are simply subject to additional switching studies to confirm their clinical similarity to the reference product. That does not mean they are more similar to the reference product than a standard biosimilar.

At the 2021 DIA Biosimilars conference held virtually this week, Dr. Cohen restated logic that may be obvious but less often discussed: if two biosimilars are deemed highly similar to the same reference product, those two biosimilars, through the Law of Transitivity, should be highly similar to each other.

Though logical, the concept of biosimilar-to-biosimilar interchangeability is not acknowledged on a regulatory basis. However, the potential for biosimilar-to-biosimilar switching is undeniably real.

Biosimilar-to-Biosimilar Switching Likely to Occur

A large proportion of patients receiving chronic therapy with biologics will no doubt change health plans or insurers over time. This happens voluntarily (e.g., they may choose a lower-price plan from year to year) or involuntarily (i.e., their employer changes the plan offering from one year to the next). These plans utilize their own drug formularies. Considering the launch of perhaps eight adalimumab biosimilars in 2023, health plans will likely prefer different preferred adalimumab products, based on the contracting offers they receive or the characteristics of the biosimilar (e.g., citrate free, high-dose formulation, interchangeable). The same can be said for insulin products, infliximab, ranibizumab, and even chronically used oncology agents. Assuming that is the case, biosimilar-to-biosimilar switching may be somewhat common in 2025.

Is that an issue? Likely not, said Dr. Cohen. He believes that any immunogenicity concern is a hypothetical argument, “and no empiric evidence exists to support the concern. Furthermore, no data has been published to support immunogenicity on a mechanistic basis.” The biosimilar is highly similar not only in efficacy and safety but also with regard to immunogenicity.

What the Data Say

Most of the available data on biosimilar switching comes from Europe, where biosimilars have accumulated over 2 billion patient treatment-days of exposure. Countries adopt whichever biosimilar has the lowest price, based on tendering systems. This may mean that more than one biosimilar is accepted, and these tenders can change from year to year. The regulatory concept of interchangeability does not exist in the EU, and switching may occur in both infusible as well as injectable agents.

Dr. Cohen pointed out that published studies of biosimilar-to-biosimilar switching, based on the European experience, amount to 12 trials, all of which used observational data. Two trials involved adalimumab, eight infliximab, one etanercept, and one involved rituximab. These totaled 1,223 patients. Additionally, 8 studies were reported as meeting abstracts, six of evaluated infliximab biosimilars, and one each for adalimumab and etanercept. Those trials totaled 1,295 patients. Although the studies varied in terms of their limitations and design rigor, they were consistent in finding no differences in patient clinical outcomes, immunogenicity, or pharmacokinetics and pharmacodynamics.

“From a scientific matter, we can trust biosimilar-to-biosimilar switching,” stated Dr. Cohen. “There have been no safety issues, and we’ll very likely have more (observational) data in upcoming years.” If the data continue to show no significant issues, “it would be reasonable to conclude that biosimilar to biosimilar switching does not have any clinical impact.”

Observational data will have to do here, as no biosimilar manufacturer would reasonably spend the money to conduct a randomized, controlled head-to-head trial with another biosimilar.

The Declining Value of Interchangeability Over Time

The inevitability of this discussion has a noteworthy effect: It lowers the value of an interchangeable designation over time. Consider the adalimumab situation, which is similar to one we posed a few years ago: A health plan decides to prefer biosimilar C, which is designed by FDA to be interchangeable to Humira®, around mid-2023. In doing so, the plan places an NDC block on the reference product, and moves to convert as many patients as possible to interchangeable biosimilar C. It achieves more than 80% conversion through substitution at the pharmacy or specialty pharmacy. However, the plan is offered a far better price in 2024 on biosimilar F, a noninterchangeable drug. Biosimilar C no longer has an interchangeability advantage. All of the patients who were converted from Humira were already converted. And biosimilar C is not considered interchangeable (by the FDA) with any approved biosimilar. Payers, however, will likely consider these agents freely switchable with each other, depending on how much weight the payer gives to citrate status and dose concentration characteristics of the products.

What does interchangeability mean in the realm of insulin products? We’ll delve into that rabbit hole in the next post.

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!

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.