By Anna Rose Welch, Editor, Biosimilar Development
After roughly four years of writing about biosimilars, I can finally say I made it to the 17th Annual Biosimilar Medicines Conference. The conference took place March 28 and 29 in Amsterdam, the (new) home of the European Medicines Agency and the “rolling grounds” of roughly 1 million bicycles. (Truly, I have never seen more determined bicyclists in my life.) Not only was I lucky enough to have a few days prior to the conference to experience Amsterdam but I also was honored to chair the final session on the first day.
One of the draws of this particular conference for me was the line-up of speakers, which comprised experts from many stakeholder organizations — even ones that typically aren’t acknowledged during industry conferences. These include patients and physicians. But I also appreciated the attention paid to specialists in the procurement sector. There was also an impressive collection of regulators from different nations and regional and national health experts from countries across the EU.
Some of the discussions over the course of the two days went as I expected they would. The U.S. remains an enigma, one that, as a born-and-bred American, I reserved the right to laugh at incredulously and shake my head whenever someone asked how things are going in our healthcare system. (Our Rubik’s Cube, more like.) During the anonymous (key word here) audience poll questions, it was clear there remains great angst about slow regulatory convergence and single-winner tenders, along with patent thickets, misinformation, and price dumping, among other acts of innovator misbehavior.
But this conference was also valuable to get a closer look at Europe as well, not only to see where things are working, but also where they’re not. Those of us in the U.S. are used to labeling the EU one giant biosimilar success case. While I’d argue this is true compared to the U.S., it’s also important to acknowledge that the situation overseas is more nuanced than it may appear. During one presentation, an expert expressed how struck they were by the variety of different policies, procurement practices, uptake levels, costs, and cost erosions across the EU nations — despite the fact the EU is united by a single regulator. In fact, even on a granular level, looking at countries regionally will turn up strikingly different levels of success with biosimilars (or lack there-of).
For example, as one expert from Spain discussed, after realizing their particular healthcare system’s low uptake, prescription quotas and biosimilar flat-rates were implemented. This, in turn, increased biosimilar usage from 9 to 11 percent. This may not seem like a lot, but for that particular system, an uptick of 2 percent is worthy of a fairly good-sized cake and some champagne. It’s also further proof that countries and healthcare systems need to put parameters in place to guide and encourage biosimilar use overall. (Honestly, I was surprised to hear quite a few speakers from different countries approach the microphone and share that their countries did not have national biosimilar policies in place. I was operating, perhaps naively, under the assumption these policies were more common.)
Like many conferences I have attended, the amount of information I took in at this one was overwhelmingly good, and, therefore, it was hard to pick a focus for this broader take away article. So, by a difficult process of elimination, I’ve arrived at three topics that, no doubt, will arise in future articles about the individual panels.
Biosimilars And Therapeutic Innovation: Why They Go Hand-In-Hand
For years we’ve talked about biosimilars primarily from a savings standpoint. The savings from these products can free up healthcare funds to tackle more innovative treatments and improve care at the hospital level (via gainsharing), and the lower costs of biosimilars have increased patients’ use of biologics.
But as I came to realize at this conference, there is something to be said about how biosimilars can alter the overall treatment pathway for physicians and patients, as well. This remains a topic we never hear broached in the U.S. — one I’d argue could be beneficial to include in patient- and physician-facing educational efforts.
Though we certainly can’t overlook the savings across the EU thanks to biosimilars, one of the most common words proclaimed by panelists at this conference was “access.” (I’d argue it was brought up more often than cost savings.) As patients gain earlier access to biologic treatments in the course of their diseases, this raises important questions about the long-term impact biosimilars can have.
As one physician argued, biologics no longer need to be reserved for the most severe cases of a disease, nor can biologics be impactful only from a maintenance therapy standpoint. As cheaper biosimilars enter the market, patients and healthcare systems finally can prioritize biologic treatments earlier than ever. Therefore, the question arises: could early, active intervention via a biosimilar modify the disease state? According to one oncologist, the answer is yes, at least in breast cancer treatment.
Though the experts admitted more evidence is needed to determine the big-picture answers, they posed questions around whether earlier access to a biologic (via a biosimilar) could slow the disease and halt the damaging effects or wear it can have on the body. This earlier access could, in turn, improve quality of life and physical well-being of a patient and lower the danger of comorbidities. (Now, of course, a big issue standing in the way of earlier use is physician and general practitioner education about biosimilars.)
So often, biosimilars are pegged as a disruptive force “interrupting” treatment with an originator. But as the panel of physicians discussed in depth at the conference, biosimilars can introduce potential changes to the clinical treatment pathway and, in several ways, biosimilar development can answer questions the innovator drug has not.
Procurement: With Great Power Comes Great Responsibility
Procurement remains one of those topics central to every biosimilar market update we receive; but, overall, there are rarely any deep dives into the best (and worst) practices in purchasing medicines. Hence, why I was so happy to see an entire panel dedicated to how the industry can develop a sustainable procurement process for biosimilars.
As one speaker put it best, buyers of medicines have great power, and with that comes great responsibility. (Cue Voltaire, or, if it floats your boat, Peter Parker’s Uncle Ben.) How buyers choose to purchase a treatment, which criteria they use to select products, and how many allotments are permitted all shape how manufacturers approach and invest in supply for each of the target markets. And though the impact of these decisions may not be felt immediately, they are felt over the course of the following five to 10 years. Hence the repeated declaration throughout the panel that procurement is an art form, and, therefore, requires training, a critical eye, and ongoing revision.
One of the key questions addressed during the panel was what a sustainable procurement system looks like and what elements go into creating that model. As was no surprise, multi-winner tenders were much preferred to the single-winner tenders that have often enforced race-to-the-bottom, short-term mindsets. This was elaborated upon perfectly in an IQVIA report published a few months ago which outlined best practices for achieving long-term sustainability in the biosimilar market. As was discussed throughout the entire panel on procurement, a sustainable market will, ideally, leverage incentives to promote biosimilar use while still permitting physicians their prescribing power. Similarly, tenders need to be crafted to permit multiple winners a crack at the market without a purchaser’s sole product selection criteria being built around price. Though the phrase “everyone gets a trophy” has negative connotations, in the procurement realm, this is something the industry must fight for. As one expert summed it up best, long-term sustainability ideally will mean that biosimilars aren’t used simply to drive the innovator down in price and then cast aside (which is happening in some markets) and that contracts ensure each stakeholder receives some benefit.
Now, how each country does this will differ, of course. We cannot expect each country will nor can adapt the successful procurement practice of another country, and it will surely vary molecule by molecule. There are many nuances to consider in each system. For instance, I found it interesting to hear more about manufacturer needs in the procurement process, including more lead time to ensure supply following a tender decision, as well as transparency over the volumes allocated to each company. Smaller countries that may have multiple tender processes a year, for example, can pose a particular challenge for companies.
It may be well known amongst the manufacturing community, but it’s perhaps less known among procurement specialists, that there are fewer facilities capable of producing biological products than there are small molecules. Between this and the longer time frame needed to manage cell lines in bioprocessing, some manufacturers can find themselves competing against affiliates of their own company for stock in certain countries. From a manufacturer perspective, this will be another factor that needs to be considered during the procurement process and deserves a place in the ongoing dialogue with procurement specialists surrounding sustainability.
Sustainability Requires More Nuanced Discussion Of Clinical Trials
Of course, we cannot discuss sustainability without doing a deep dive into the regulatory process. The discussion at this conference was by far one of the best, most thorough debates I’ve heard on the state of, and needed evolutions in, the biosimilar regulatory pathway. As we encounter ongoing innovations in drug development, including orphan drugs and cell and gene therapies, there will need to be advancements and changes in the biosimilar regulatory pathway to ensure future competition in these classes of medicines.
I’ll admit, coming from the U.S. where we seem to be moving backward as opposed to forward in certain regulatory areas, I was expecting to see more comfort with biosimilar regulatory evolutions amongst global regulators. It turns out there’s still a good dose of caution. But I was appreciative of the rich discussion that followed about some of the trickier, more technical questions that have arisen over the past few years. To have or not to have clinical trials is often presented as a black-and-white issue. But the solution — at least in the foreseeable future — will likely be a shade of grey. We might not see the outright elimination of Phase 3 clinical trials for all molecules any time soon, but the hope is that we’ll discover how better to use Phase 3 trials to answer questions about differences that may exist between the biosimilar and its reference product.
For instance, a topic brought up multiple times was the drifts in antibody-dependent cell-mediated cytotoxicity (ADCC)-related critical quality attributes (CQAs) in the reference drug Herceptin. This shift was uncovered in several lots of the reference product during the development of the biosimilar. As one regulator pointed out, analytically, the biosimilar showed similarity to the reference product, while clinically, it actually demonstrated superiority. (Surprise! As a reminder, a biosimilar can only be as good — or bad — as its reference product.) Therefore, several of the panel members emphasized the need to better understand the CQAs of biologics (including biosimilars) and which will be most important clinically.
In the case of Herceptin, for instance, the role the ADCC quality attribute played in the drug’s mechanism of action was not previously understood. As such, some regulators expressed concerns that we cannot yet tailor biosimilar clinical trials — at least not for all molecules — based solely on analytical data without greater understanding of which attributes will be most impactful to the drug’s clinical profile. Much of this understanding will come down to the proper assay selection, which helps determine the most meaningful and relevant differences. However, this is no mean feat and raises the question of what a relevant difference may be. As you can expect, this will also vary amongst molecules and patient populations.
The ongoing emphasis on larger Phase 3 biosimilar clinical development also stimulated some impassioned discussion on the benefits and inherent limitations of clinical trials overall. For instance, one expert acknowledged that clinical trials are a wonderful tool, but they still can be prone to variability. In some cases today, biosimilar trials — thanks to their sample sizes — can introduce more questions than answers. Phase 3 trials certainly may be capable of picking up large and dramatic differences in a biosimilar’s clinical performance. But the likelihood these dramatic differences would not be revealed through analytical characterization is slim.
It should go without saying that biosimilars must not be held to a higher regulatory standard than their reference products. The manufacturing change and ADCC shift in Herceptin is the perfect example in which a certain amount of analytical data was likely reviewed and approved by the regulator following the originator’s manufacturing shift. However, regulators on the panel were unable to answer what clinical data the originator provided to the agency (or even if clinical data was submitted) to approve the Herceptin manufacturing change.
Though there were many different definitions for a “tailored biosimilar approach” brought up during the conference, I appreciated one in particular. As one expert described, perhaps a tailored approach means taking a more rational and prioritized approach in linking analytical data to the risk profile of a drug. While trastuzumab and rituximab might, for example, be classified as higher-risk molecules which require more scrutiny when interpreting the analytical data, not as much caution is needed when interpreting analytical data for certain products like adalimumab. Ultimately, this kind of analysis could introduce a bit more freedom and movement into the development and regulatory process of biosimilars as we move forward to what must be (and, I dare say, eventually will be) a more tailored future.