From The Editor | December 26, 2018

Why 2018 Was The Year Of Real-World Evidence

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

Biosimilar Industry

At the beginning of 2017, I published an article based on an interview with HoUng Kim of Celltrion (now a member of the Biosimilar Development editorial board). At the time of the interview — December of 2016 — the industry was still hyped about the release of the first highly anticipated switching study, The NOR-SWITCH study. This was the first study of its kind to be released, and we didn’t know how it could influence future education efforts and squelch fear-mongering. At that time, we were only starting to enter the age of real-world evidence (RWE).  Indeed, one of the things that stuck with me throughout the interview with Kim was his emphasis that the industry’s success in 2017 hinged on the industry’s generation of and transparency about data.

As we approach 2019, it’s clear to me that the biosimilar industry has taken this need to heart, especially over the past year. At a conference in Brazil in August, I was asked to present on the RWE efforts I felt were particularly notable. In doing the research for this presentation, my eyes were opened to the pace at which biosimilar evidence is being released.

On one of my first slides, I included a list of eight articles, all of which boasted headlines pertaining to biosimilar-related studies. All eight of these articles, which highlighted switching study results or real-world studies spanning six different countries, were reported over a period of seven weeks. That’s more than two articles a week showcasing the safety and efficacy of biosimilars.

But what I liked about this exercise was that it gave me a sense of the broader trends in the industry’s growth. We no longer just need reports on safety and efficacy, and we’ve long passed the days when that’s the only kind of data we can report when it comes to biosimilars and their impact. We also need to know how exactly these products are functioning within the broader healthcare industry. Thanks to greater uptake around the world, we are more equipped to do this. In the first of what will be two articles on this topic, I unpack some of the most impactful real-world evidence releases or efforts implemented over the past year, as well as which of the biggest biosimilar questions were answered over the past year.

How Established Is Our Baseline Of Knowledge?

As I’ve discussed in the past, there are certain initiatives or studies that have bolstered this industry’s clout and established new baselines of knowledge. The NOR-SWITCH study was the first of its kind and provided a significant leg-up for the industry. But we also knew, and as was confirmed by the lingering concerns from gastroenterology stakeholders, this certainly wouldn’t be enough to win over what has been — and to some extent remains — a skeptical stakeholder base. 

But if any questions about switching persisted between the release of the 2016 NOR-SWITCH Study and 2018 (and they certainly persisted), this past year has provided some great clarity. In March, a literature review was released that was both a cause for celebration as well as a wake-up call alerting us of just how far we have come (even if it doesn’t feel like it). After reviewing 90 switching studies (yes, there have been at least that many), several experts came to the conclusion that concerns about safety and efficacy following a switch to the biosimilar remain hypothetical. These studies investigated different molecules; they varied in population size and took place in multiple countries. There were also two multiple-switch studies included in the review. Just as the NOR-SWITCH study raised the bar on our knowledge of infliximab transitions (the most complex mAb biosimilar we’d faced that far in 2016), so too did this literature review, which reinforced the safety and efficacy profiles of biosimilars despite the variability of the studies examined.  

But even the soundest of reviews or studies are bound to raise a few questions (or attempted diversions). A few months after the literature review’s publication, several scientists from Janssen, the makers of Remicade, penned a letter to the editor calling into question several aspects of the review. Though some of their methods of data-picking raised significant ethical questions, their questions do offer the biosimilar industry some critical benefits. Not only did it give the lit review authors another opportunity to emphasize the strength of their data (which they did), but it also introduced areas of inquiry that could continue to make the biosimilar industry and its future RWE increasingly water-tight.

For example, it (indirectly) pointed out the need for additional literature in physicians' journals about the concept of manufacturing changes and the impact this can have on biologic molecules over time. There were also questions about discontinuation rates in certain studies, which could use additional attention as patients and physicians grow more comfortable with biosimilars (and, hopefully, less impacted by potential “Nocebo” effects). If we know anything, doubt and skepticism over biosimilarity only serves to weaken their overall performance in patients.  

How Has Our Biosimilar Knowledge Grown Over 2018?

Though both the NOR-SWITCH study and the literature review of the 90 switching studies may have (still) left some with questions, I’d argue these lingering questions were put to rest over the course of this year. For instance, the role of infliximab biosimilars in gastroenterology was one of the first biggest concerns following the approval of infliximab biosimilars — and it continues even today. Extrapolation has become much less of a concern over time, though it certainly hasn’t been eradicated. For those who hold onto efficacy concerns in the gastro indications (especially due to a lack of understanding of extrapolation), a French equivalent study was published recently in the Annals of Internal Medicine.

In this study, 5,050 infliximab-naïve patients were started on either the reference product or CTP-13 (Remsima). Following the completion of the comparative equivalence cohort study, the researchers concluded that CTP-13 was equivalent to Remicade in treating Crohn’s disease in infliximab-naïve patients.

In what I consider to be another similar milestone, there was also a study published earlier this fall in the World Journal of Gastroenterology which supports the use of biosimilar infliximab in pediatric patients. Given Remicade’s ongoing exclusivity for pediatric patients in the U.S., biosimilars to-date have yet to reach this patient population. But there have been several studies undertaken in Poland, the U.K., and South Korea to determine the impact of biosimilars on inflammatory bowel disorder (IBD) in children. Though data remains limited to-date, the researchers concluded infliximab was equivalent to Remicade in treating this population.

In addition to these studies adding to our base of knowledge in certain indications or populations, I was also heartened by the release of a second, though less extensive literature review of single-switch trials involving Remicade and Renflexis, Remsima/Inflectra, and BOW015 (Epirus’ former biosimilar candidate). After digging into 36 studies and 34 abstracts, researchers singled out 13 publications detailing six randomized controlled single-switch studies in rheumatoid arthritis (RA) that took place between 2004 and 2018. After reviewing these studies, researchers once again affirmed the safety and efficacy of a single transition from the reference to the biosimilar.

You might ask why I find this particular study worth highlighting (and being giddy about). It was sponsored by Janssen. Given the Letter to the Editor submitted following the 90 switching studies literature review, as well as the industry’s general concerns about this originator’s educational strategies about non-interchangeable biosimilars, it was cathartic to see positive biosimilar news related to some of their efforts.

Now, this review surely won’t end all innovator-related mischief. Afterall, a common line of inquiry now has to do with multiple switches — and, perhaps even more prominently, biosimilar-to-biosimilar switching. Indeed, the authors of this Janssen-sponsored review did point out that their evidence was only reflective of single-transitions only; multiple switches and biosimilar-to-biosimilar switching remains to be extensively studied. But after some innovators’ efforts to distort biosimilar safety and efficacy, it was refreshing to see a positive biosimilar study published and associated with one of the most competitive reference product companies to-date.

Stay tuned for part 2 on some of the remaining questions raised by RWE in 2018, as well as some of the upcoming RWE trends.