From The Editor | November 8, 2019

EMA Update: What Challenges Are Biosimilars Bringing To The Table?

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By Anna Rose Welch, Director, Cell & Gene Collaborative
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Biosimilar Industry

As a member of the 2019 DIA Biosimilars Conference planning committee this year, I got a front-row seat to the wide array of potential speakers and topics we hoped to feature during September’s event. Because I tend to engage more regularly on the market access side of things, I’m well aware of how passionately many in the industry feel about creating the appropriate policies and market access mechanisms to get biosimilars swiftly into patient’s hands. But it never fails to surprise me just how delightfully fiery the scientific and regulatory side of this industry can be, as well. A large portion of our bi-weekly committee calls led to long discussions about the regulatory landscape, and there was great excitement upon confirming Dr. Elena Wolff-Holz, chair of the EMA’s Biosimilar Medicinal Products Working Party (BMWP), as one of the speakers.

The timing of the DIA meeting was perfect, given that a highly anticipated and (hopefully) game-changing publication by Wolff-Holz debuted in BioDrugs in late September, just three days before the DIA conference. In her paper, “The Evolution of the EU Biosimilar Framework: Past and Future,” Wolff-Holz lays bare the analytical and scientific learnings we’ve gleaned thus far from EU biosimilar approvals over the past seven years, as well as how these insights could impact the overall biosimilar development pathway. (Though it was not an official companion piece, Chris Webster’s and Gillian Woollett’s publication, also in BioDrugs, on a proposed paradigm shift away from “totality of evidence” to “confirmation of sufficient likeness” [CSL] is quite complementary to Wolff-Holz’s paper and is worth a gander, as well.)

The topic of biosimilar regulatory reform has become even more intense in the past few years, especially as biosimilar prices continue to lower in Europe and the U.S. market remains stilted. Given the real-world evidence accumulated in biosimilars’ favor, as well as the pressure firms are facing in uncertain markets, many argue we’re at the point we can decrease our reliance on costly clinical equivalence trials to promote long-term development and market sustainability.

Of course, as much as we’d like to see swift regulatory advancements, papers such as Wolff-Holz’s and Webster’s and Woollett’s will most likely (first) encourage more discussion and debate before any substantial changes are enacted. Having listened to Wolff-Holz’s DIA presentation on biosimilar updates out of the EMA, it’s clear there’s lots of work to do in other areas outside of fine-tuning regulatory pathway requirements. But we’ve come a long ways. Altogether, there were several topics she brought up that stood out, either as bright spots to boost industry morale, or that emphasized where the industry needs to focus its energy to pave the way for future regulatory reform.

EMA Progress: A Brief Look At The Numbers

As of September 2019, the EMA has had 92 market access applications (MAAs) cross its desk. Eighty of these have been reviewed; the12 awaiting a final decision comprise multiple applications for rituximabs, teriparatides, and trastuzumabs, along with individual MAAs for insulin aspartate, adalimumab, bevacizumab, and etanercept. So far, this industry has celebrated a whopping 61 MAA positive opinions, and there are 54 biosimilars currently on the market for 15 different products. There have only been two products rejected by the agency prior to approval and seven products withdrawn post-approval.

Currently, the bulk of the agency’s time is being spent reviewing MAAs and providing scientific advice, Wolff-Holz said. In fact, the EMA faces upwards of 650 scientific advice proceedings per year — and that number only continues to trend upwards. The regulators meet 10 times a year. There are generally three to six biosimilars discussed per meeting, which accounts for anywhere from 5 percent to 8 percent of the EMA’s scientific advice workload.

Though publishing conceptual guidelines is an important part of a regulatory agency’s work, the EMA is momentarily short-staffed, meaning regulators have had to prioritize advancing products through the MAA process. Following the move from London to Amsterdam, the agency lost 25 percent of its workforce — a toll that was greater than initially anticipated, Wolff-Holz admitted. Though it’s unclear how long the employee shortage will last, the agency is in the process of hiring new staff and will be moving into its official, permanent Amsterdam location in January 2020.   

Regulatory Convergence, Broader Biosimilar Education Top Of Mind

Over the last few weeks, there have been a lot of conversations on my LinkedIn newsfeed and in the news surrounding efforts to promote greater regulatory alignment, specifically amongst stringent regulatory authorities. The latest call to action was in a presentation by the International Generics and Biosimilar Association (IGBA) at the Association for Accessible Medicines’ GRx+ Biosimilars conference.

As RAPS shared in a writeup of this presentation, the acceptance of foreign sourced reference products demands greater regulatory convergence, given the different stipulations from nation to nation. The IGBA is also pushing for public transparency into certain regulatory alignment initiatives — for example, the work being done by the FDA’s Biosimilars Cluster — and greater willingness on the part of regulators to (privately) share unredacted assessment reports amongst themselves.

In her presentation at DIA, Wolff-Holz acknowledged that “broader encouragement of global biosimilar regulatory convergence” is a factor that will enable the EMA to realize the goals in its draft Regulatory Science To 2025 strategy. As you may have assumed, one of these goals is to advance patient-centered access to medicines in partnership with healthcare systems. Though it’s easy to label the entirety of Europe a biosimilar success story, simply because of the uptake levels and overall savings compared to the U.S. market, Wolff-Holz reminded that the EU uptake patterns of biosimilars across the different countries are quite heterogenous. One of the keys to greater uptake across the board is to ensure each member state is on the same page when it comes to biosimilars.

Given the differing levels of biosimilar awareness in the various EU countries, Wolff-Holz talked about the agency’s efforts to ensure educational efforts are more wide-spread. As she shared, upwards of one-half of the national competent authorities (NCAs) have no information about biosimilars on their individual websites. Overall, the EMA has been quite proactive in terms of biosimilar education; not only has it posted an informational video in all the European languages to its website, but it’s also begun to fine-tune its education on certain molecules. Wolff-Holz shared that it’s begun to elaborate more upon the benefit/risk profile of biosimilars, as well as dedicating more effort to presenting visual aids explaining quality attributes of molecules, which remains one of the least understood elements of all biologic drugs amongst patients and providers. Moving forward, the EMA hopes to collaborate even more closely with the NCAs to help collaboratively address each regulators’ and country’s information needs around biosimilars.  

It was also reassuring to hear that the agency continues to address efforts by originator companies to disparage or imply that biosimilar treatments are to be approached with caution. She shared one example, in fact, in which an originator made claims that its product Perjeta must only be used in combination with the brand Herceptin (though biosimilars are available for trastuzumab). The agency is working with the innovator to ensure the label is written appropriately moving forward.    

The Industry Embracing Future Pipeline Waves & Challenges

In March 2019, I had the pleasure of moderating a panel at the Biosimilar Medicines Conference in Amsterdam. The goal of the discussion, which took place between representatives of several different stakeholder groups, was to lay out what was needed to ensure a more sustainable biosimilar future. It’s no secret that, if we look at the current wave of biosimilars, quite a few of them are large volume, blockbuster treatments. But many of the prime candidates for future biosimilars are for smaller or orphan patient populations. Though one industry expert shared that there is no shortage of scientific or altruistic desire amongst biosimilar makers to explore these products, the question remains whether there will be a place in the market 10 years down the line for biosimilar makers to play in these spaces — especially given the investment demands of the current biosimilar development paradigm. This question remains relevant today. (A great article on the challenges of orphan drug biosimilar development can be found here.)

That’s why I was particularly happy to hear confirmation from Wolff-Holz at DIA that there is interest in biosimilar development of orphan drugs in addition to several other important categories of biologics/patient populations. As Wolff-Holz shared, along with biosimilars for orphan drugs, manufacturers are engaging the EMA for scientific advice surrounding the development of biosimilars used solely in pediatric populations, biosimilars of products with marginal effects, and biosimilars used in combination with other medicines. There are also discussions around biosimilars of disease prevention agents and of products with low systemic serum concentrations. Conversations occurring around these potential future biosimilars include trial endpoint selection, the overall feasibility of randomized, controlled trials/comparability trials (specifically for combination treatments), and finding and defining PD markers, to list a few.

At the heart of this discussion, however, I appreciated Wolff-Holz’s acknowledgement of the continued scientific learnings and possibilities for regulatory advancements. “We are getting interesting scientific advice requests that are pushing the system,” she said. “This demonstrates that science is a living thing — it advances. We have initial guidelines we publish, but they are fed into by the learnings from scientific advice procedures which then move into the clinical development plans and the marketing authorization applications. This all feeds back into the system. I can foresee that, even now, there are some guidelines that will need revision sometime soon.”

The Current Hang-Ups In Tailored Biosimilar Development

At the conclusion of Wolff-Holz’s BioDrug’s paper she writes, “With increased experience and analytical capabilities, and with progressive knowledge of structure-function relationships and disease-specific mechanisms of actions of therapeutic proteins, a continuing reduction in clinical data requirements for biosimilar developments can be foreseen.” (Cue fireworks and/or glorious images of sunrises over mountains.) Those of you who have been following the regulatory discussions will know just how momentous of a declaration this statement is.

But as was emphasized, not all regulators are necessarily on the same page, despite the fact Wolff-Holz acknowledged in many cases regulators and colleagues urging for regulatory reform are “thinking along similar paths.” At conferences I’ve attended over the past year, it’s been clear that regulators are keenly aware of just how much technology has advanced to give us the best possible insights into both the originator and biosimilar molecules. But as regulators have discussed in the past — and Wolff-Holz emphasized at DIA — the better you know a molecule, the more differences you can observe between molecules. While most regulators would agree that they can determine whether a molecule is highly similar by examining the physical-chemical characteristics of each molecule, the debate lies within the functional assays. In fact, given the challenges the EMA observed in its pilot program for tailored development, regulators are concerned more work needs to be done to better understand the quality attributes and the role they play in the mechanism of action for complex antibodies.

As I’ve written before, many of the manufacturers approaching the regulators in the pilot program have presented immature quality data. Wolff-Holz shared that, in the six applications thus far, manufacturers have not followed the step-wise approach to development. In some cases, companies began running clinical trials in parallel with their quality and functional assessments. “We’re getting very conceptual quality data,” she explained. “We then are hesitant to give more forward-looking advice about whether or not they need a clinical trial.”  

In addition to potentially adding additional slots for manufacturers in this pilot program (there originally was just room for six), Wolff-Holz added that the regulators have established a functional assay group as part of the BMWP. This group is exploring the mechanisms of action for the complex monoclonal antibodies. In doing so, they can determine the appropriate validation procedures and any possible PD markers for certain molecules that could decrease the need for a larger equivalence trial.

Though the effort so far has only yielded what Wolff-Holz referred to as “encyclopedic information,” in the long-term, regulators plan to catalogue which functional assays will be the most important for manufacturers to carry out on their specific molecules.

“We want to look at the different antibodies and be able to say, ‘Alright, in looking at all these products that have been approved, which assays were used? What were the critical quality attributes we established?’ That way, when a manufacturer prepares its development program, we can say these assays must be there and they must be right. Otherwise, we will go back and ask more questions that will require the use of additional orthogonal methods to address our uncertainties.”