From The Editor | December 19, 2017

What U.S. Biosimilar "Traditions" Need To Be Broken In 2018?

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By Anna Rose Welch, Editor, Biosimilar Development
Follow Me On Twitter @AnnaRoseWelch

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A few years ago at a biosimilar conference, a speaker said something that has stuck with me ever since: As the market moves forward, “Biosimilar companies have to ask where the market is going and when they will need to break from tradition and think about different models for some of their products.”

There are a number of ways this statement can be addressed, and depending on what position you hold within the industry, your thoughts will likely be drastically different. If we look at the biosimilar space as a whole, I’d argue it’s already been actively breaking from tradition in several broad ways. In the past year alone, the space has been at the heart of a greater push for supply chain and payer-contracting transparency, policies addressing risk evaluation and mitigation strategies (REMS) abuses, and reimbursement policy revisions. The J&J and Pfizer lawsuit has thrown into question traditional methods for brand-to-brand formulary competition, and the contentious Medicare Part B policy has been overhauled.

It goes without saying that the biosimilar market in the U.S. is still emerging. Even the EU, which is a decade ahead of the U.S., is just being introduced to some of the more complex mAb biosimilars. As such, you may feel “tradition” is not yet a realized concept in the biosimilar industry — and I would agree with you. But this didn’t stop me from asking several experts which areas they felt could stand more attention or redirection in the future. And they left no stone unturned.

Current State Of Regulatory Policies: Cause For Concern?

So far in the U.S., everything from regulatory affairs to reimbursement policies has been in a state of flux. In fact, as Peter Moesta, CEO of Adello Biologics, articulated, what needs to happen within the next year is perhaps less of a “break from tradition” as it is “a general evolution in collective thinking and comfort with biosimilars.” There is certainly truth to this — the industry needs more time to evolve in the areas of education, stakeholder comfort, and payer uptake. (However, as I discussed in a recent article, uptake needs to evolve from being a watch-and-wait situation for both manufacturers and payers.)

But there are also some aspects of this industry with which we’ve grown increasingly familiar that could stand for a bit of a (positive) shake-up to move the industry forward. As Gillian Woollett, SVP of Avalere Health, shared, one big concern she has is that many anti-biosimilar campaigns have made regulatory agencies, and especially the FDA, more cautious. This caution is also translating into sponsor companies’ regulatory strategies. In fact, as she describes, “This overly cautious regulatory environment may impact our collective ability to get originator products to patients, too, not just biosimilars. Typically, we know the least about the innovator product upon its initial approval.” (And the FDA has acknowledged this was the case with many of the originator biologics that biosimilar makers are targeting today.)

One such example of this excess caution is the rhetoric about immunogenicity and fear of switching patients from the innovator to a biosimilar (or vice versa). There are some issues with these arguments from a scientific standpoint, especially when we consider the process innovators go through to demonstrate the originator molecules remain comparable following a manufacturing change. “Comparability has been used in support of manufacturing changes for 20 years on the same active moieties biosimilars are sharing now, and we’ve rarely seen any problems at all,” Woollett said. (The only product that caused some issues was an originator drug, Eprex [epoetin alfa], in the EU, and I’ve heard from industry members in-the-know that this problem was actually linked back to the product’s packaging — specifically the vial’s rubber stopper.) 

Obviously, the topic of comparability is, generally speaking, “in the weeds” for those outside of drug development, like patients and physicians. But, it’s important to note that comparability is not publicly discussed in the U.S., unlike in the EU where comparability practices following a manufacturing change are shared publicly. As such, patients and providers in the U.S. are unaware any (clinically non-meaningful) changes to the innovator products occur following manufacturing changes because this information is not added to the label.

It’s the successful use of comparability following manufacturing changes that has informed Woollett’s own concerns about the FDA’s decision to regulate interchangeability. A biosimilar’s analytical comparability data needs to be coupled with clinical trial data and, in the case of interchangeability, multiple switching studies. But, “When we use comparability for an innovative biologic, the pre- and post-change products are automatically interchangeable with themselves,” she pointed out. “There is always extrapolation between all indications — the label doesn’t change.”   

Brand, Generic, Or Neither: Establishing A Biosimilar Commercialization Blueprint

In addition to extensive regulatory hurdles, there are clearly some shake-ups needed in the commercialization landscape. After all, of the eight biosimilars approved thus far in the U.S., only three have been launched (and much of this has to do with patent challenges). Prior to the launch of biosimilars, there were two dominant business models for a pharmaceutical product — brand and generic. When biosimilars first launched, a number of stakeholders likely expected them to fit into the generic business model. In fact, payers’, patients’, and physicians’ ongoing desires to see steep discounts right away suggest there are still expectations for biosimilars to embody a more generic-like business model.

But in the wake of Medicare Part B and Part D revisions, new naming policies, and the intense focus on patient assistance programs (which generics don’t have), biosimilar companies are dedicated to carving out their own commercialization blueprint. Though price is destined to be a large part of a biosimilar’s appeal, a central challenge to establishing a commercialization model is to create additional market drivers outside of price. And patient assistance programs — a key area for differentiation — would be one of the first areas impacted in an environment solely dictated by price. (This was just one reason the revision to Medicare Part B is being celebrated by stakeholders and manufacturers alike.)

As Mark Langston, executive director, biosimilars marketing for Boehringer Ingelheim, said, “By their very nature, biosimilars break from tradition when compared to branded biologics. Companies typically focus marketing efforts around differentiating their products from competitors. But for biosimilar manufacturers, however, the goal is to demonstrate biosimilarity, meaning there are no clinically meaningful differences from an existing FDA-approved reference product.”

The key to differentiating themselves from other biosimilar makers (and innovators, for that matter), Langston argued, is by committing to the overall patient experience “from the day a person aligns on their treatment plan with their healthcare provider to when they start using that treatment.”

Overall, a number of the experts I reached out to emphasized the importance (and possibility) of having more than two commercial models in the marketplace, especially if biosimilars offer a variety of new approaches to reach and aid patients in different care settings. A common argument made is that improved devices and patient services may be more beneficial to patients with chronic conditions outside of cancer. However, I recently learned how important these services are in the oncology space as well, which I plan to explore in a forthcoming article. Stay tuned!

Legal Hijinks Require Fresh Eyes

This wouldn’t be an article about market evolutions in the biosimilar space if we didn’t touch upon patent challenges. I’ve spent the past few days looking into the litigation landscape to get a sense of where players in the midst of litigation stand as we move into 2018. I’ll admit, the companies’ responses to each other’s claims proved to be immensely entertaining at times. But they also revealed elaborate mazes of claims, motions, stays, discoveries, injunctions, bifurcations, and other legal strategies that require months of additional work and money from the companies.

In my reviews, I came across what you’d expect: Defenses of specific manufacturing processes to show certain patents aren’t actually infringed. But I’ve also been greeted with arguments that extend beyond patents and/or Inter Partes Review (IPR) proceedings claiming obviousness. There have been claims of innovators switching positions multiple times mid-trial (over the course of several years), introducing scores of new evidence mid-trial, and regularly requesting irrelevant additional information — sometimes on highly confidential marketing, commercialization, and regulatory strategies.

If we look at 2017 from a patent standpoint, we saw our first settlement between Mylan and Genentech/Roche, essentially opening the U.S. market to Mylan’s and Biocon’s recently approved trastuzumab, Ogivri. There was also the Amgen and AbbVie settlement, which has pushed back Amjevita’s U.S. market launch until January 2023. These are only the start of what I expect will be a number of settlements in the upcoming years as the costs of litigation become more prohibitive.  

The costs of litigation and the impact these will have on developers are particularly concerning to Chris Isler and Magnus Franzen, life science experts from PA Consulting Group. Franzen outlined a scenario in which excessive delays from patent challenges ultimately impact a company’s margins and, in the end, the price at which the company is able to launch its biosimilar. Though companies are striving to define biosimilars by more than just price, the price tag is still integral in determining a product’s market share and the speed of uptake. 

As Franzen described, “Some executives we speak to are talking about a one-month window for reaching the market to put you on the right or wrong side of a successful business case for biosimilar development. Imagine the effect if a launch is delayed by three to six months or even years. This could have a domino effect where patent challenges delay market launch and increase the cost of market entry, in turn impacting the margins that a company can play with when setting a price.”

For some molecules, specifically Humira, Isler and Franzen argued the patent estate defense strategy raises questions about the current patenting system. “If the U.S. wants a healthy biosimilar market, it will have to address the current possibilities of protecting innovator drugs with multiple patents,” said Isler. “Though this is difficult for an individual company to address in the short-term, in the longer-term, biosimilar companies can continue to demonstrate the value biosimilars bring to society and patients by increasing access to affordable medication. By doing so, it will become increasingly difficult to say that the barriers of extensive patent estates are acceptable.” 

Overall, these experts hit upon several areas where several overarching systems — whether they be legal, commercial, or regulatory — have posed additional challenges for the biosimilar industry. There are no easy answers here, and I can only imagine that solutions will result in compromises on both the innovator and biosimilar sides. Though it may be too early in the biosimilar space for there to be “traditions,” given the fragile nature of the U.S. biosimilar market to-date, it’s important to stay on top of these broader areas as they take shape. The industry may feel like its evolving relatively quickly (and it is definitely full of many delightful twists and turns). But, in the end, any evolutions to these larger areas will require sustained attention and effort.