By Anna Rose Welch, Director, Cell & Gene Collaborative
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As the biosimilar industry continues to advance, there has been much conversation about the role comparative efficacy studies play — or should play — in demonstrating biosimilarity. This will remain an ongoing discussion in the years ahead and could pave the way for some exciting changes in the biosimilar regulatory paradigm.
However, as the industry and regulatory agencies iron out what this paradigm could look like in the future, I wanted to learn more about the clinical considerations facing companies today. Though managing biosimilar clinical trials doesn’t often appear on conference agendas, that hardly means there aren’t a fair share of challenges. In fact, as Joan Meyer, executive director, Covance, shared at the recent World Biosimilars Congress, biosimilars are often competing with multiple other biosimilar candidates and novel treatments for the same patients. Given the many alluring innovative products in development today, it can also be tricky to recruit willing investigators and sites.
Following her presentation at the World Biosimilar Congress, I followed up with Meyer and her colleague Alicia Baker, executive strategist and head of Covance’s Biosimilars Center of Excellence. Together, they walked me through how sponsors are approaching clinical trials today and how these efforts could evolve as the biosimilar pipeline advances into future waves.
Learning Curves In Current Biosimilar Clinical Development
As Baker shared at the WBC Congress, Covance has worked with more than 83 sponsors on 132 biosimilars for 26 reference products. The most common biosimilar development programs have been for biosimilars to Avastin, Humira, Rituximab, and Trastuzumab. Given their experience with the current wave of biosimilar projects, one of the first questions I had for Meyer and Baker was what sponsors have learned over the past few years in carrying out their clinical development program, and where they may still be challenged.
Though one of the most commonly discussed topics over the past few years has been streamlining clinical development, both Meyer and Baker said that companies do still have a way to go in terms of thinking “outside of the box” when structuring their clinical studies. “Companies don’t quite understand yet just how flexible the clinical environment has the potential to be,” Meyer said.
For example, over the past few years, some companies have operated under the mindset that they must approach the regulatory agency with proposals for studies that examine comparative efficacy in more than one indication rather than relying on extrapolation. “If your PK study data is supportive of biosimilarity, then you should be able to go to the regulator with a plan to run one comparative efficacy study in one indication and rely on extrapolation for the rest,” she added.
Much of this thinking has jived with the abundance of caution regulators built into the biosimilar approval pathway. As Baker pointed out, regulator and provider uncertainty early in the development of biosimilars encouraged the collection of more data. Baker does see this mindset shifting today, especially given the years of positive biosimilar experience we’ve witnessed globally. Though she agrees with Meyer that there are still some companies and regulators that are more conservative, she is starting to see some “outside of the box” thinking in biosimilar development. The industry and regulators alike have become more cognizant of the importance of increasing trial efficiency and being more conscientious of patient recruitment needs.
For example, as Baker explained, more companies are striving to carry out parallel phase one and comparative efficacy studies. We’ve already seen two companies succeed in approving biosimilars for pegfilgrastim that did not have comparative efficacy studies. For biosimilars that span multiple indications — for example oncology and rheumatology — there is understanding that it isn’t in patients’ best interest to be recruited to demonstrate biosimilarity in multiple indications. It’s quite eye-opening to note the number of patients that are typically enrolled in just one indication for these studies. Comparative efficacy studies for currently approved biosimilars to Avastin, for example, enrolled between 600 and 750 patients. (Be sure to check out this recent publication which shared this data in its supplementary materials.)
Given the sheer number of treatments being developed in large indications like oncology and rheumatology, patients are currently faced with a lot of options. This is why Baker and Meyer point out that we’re seeing more biosimilar trials taking place in Eastern Europe and Latin America because innovator treatments are either not available at all or are designated as third-line therapies. “It’s an uphill battle to receive the biologic treatment, especially early on in the disease state,” Meyer said. “Carrying out biosimilar clinical studies in these regions can be a valuable portal to biologics access overall for patients.”
However, in other regions, the ongoing rush of innovation also poses challenges for biosimilar development. “It’s great to see science moving the treatment paradigms forward and creating new innovative treatment options for patients in some of these indications,” Baker offered. “However, this also makes the biosimilar testing paradigm more complicated because these treatments also need access to patients in these flooded therapeutic areas.”
How Future Wave Products Will Impact The Biosimilar Clinical Landscape
A number of future candidates for biosimilar competition target smaller patient populations, and, in turn, will also have smaller market returns than, say, that of a large volume Humira biosimilar. As the industry looks ahead at these future pipeline options, one of the questions inevitably becomes whether the current biosimilar development paradigm with large comparative clinical efficacy studies will remain sustainable. The need for price relief from biosimilars in the orphan drug space cannot be emphasized enough; however, the clinical requirements that may face biosimilar companies exploring some of these products could raise the complexity, and in turn, the cost, of these development programs. For example, Meyer explained that one of the biggest rare disease clinical-trial-related difficulties is that the patients are not centralized. “You cannot just pick a country or two and find a sufficient number of patients there to carry out your orphan drug trial,” she qualified. “There will likely only be a handful of patients per site, and in some cases, these sites are tertiary care referral centers, meaning patients have to travel long distances to participate in the trial.”
Though there has been chatter at past conferences about future regulatory guidance as it relates to orphan drug biosimilar development, Meyer is optimistic that biosimilar companies will be met with favorable regulatory requirements. Agencies have already adopted unique regulatory frameworks to support orphan drug development, given the clinical trial-related challenges they pose. A rare disease drug clinical trial will obviously look much different compared to Phase 3 trials for large patient population indications like diabetes or RA. Similarly, some of these innovative drugs have been prime candidates for conditional approval because of their small populations, meaning they were approved with a smaller set of data and their clinical efficacy was confirmed in a post-marketing study.
Overall, Meyer is less concerned that companies will struggle with development requirements for these products; rather companies need to be educating the different patient communities to prepare them for the days of biosimilar competition. While cost relief and, in turn, greater access to these treatments will no doubt be welcome in rare disease communities, there will inevitably be the same level of hesitance we’ve seen in other patient populations about the prospect of transitioning to biosimilars. Given the tight-knit patient community for rare diseases, the advocacy networks will be the best portal through which to reach patients with biosimilar education, both Baker and Meyer emphasized. Outside of sharing real-world evidence of successful transitions in other patient populations (of which, there is a lot), Meyer noted that biosimilar companies also need to approach these communities with the story of the drug. This not only includes information on how biosimilars work clinically, but also the benefit they bring to patient populations and society as a whole.
Clinical Debates For The Next Biosimilar Decade
As many have argued, the large comparative trial is hardly a great vehicle for determining the clinical impact of the very small structural differences between a biosimilar and its reference product. It’s impossible — at least in the space of this particular article — to discuss how comparative efficacy studies could become better suited to determining biosimilarity, especially because the answers would differ depending on the individual molecule and indication.
Though we cannot overlook the potential for streamlined clinical development in the upcoming years, both Baker and Meyer anticipate comparative efficacy studies will remain part of most biosimilars’ development pathways over the next five years. Because molecules vary widely in complexity, both Baker and Meyer expect that streamlining will always remain a product-by-product consideration, especially as treatments and their targets keep advancing. For example, Meyer homed in on the evolution happening in the oncology molecules on the market today. “We’re moving from tumor-targeting monoclonal antibodies to immune-system targeting monoclonal antibodies,” Meyer said. “In turn, you have different mechanisms of action that can translate into some very different safety issues.”
This is one of the reasons why we find ourselves today debating whether we should use healthy volunteers in originator and biosimilar Phase 1 studies for certain oncology candidates.
“What we’re seeing today in the innovative oncology antibody space is that many companies are not doing healthy volunteer studies,” said Baker. “There are safety concerns, but in addition, many sponsors are trying to get a read on early efficacy. By not using healthy volunteers, they are then able to get the pharmacodynamic parameters early in the Phase 1 which helps inform dose selection moving forward.”
In general, there have been a number of efforts to accelerate the development of novel oncology treatments. While it used to take 12 years to develop a novel drug, we’re starting to see the timeline decrease. When immuno-oncology drugs arrived, the timeline moved from 12 years to between five and 10 years. Gene therapies are even more accelerated.
For biosimilar companies, speed to market and managing cost of goods is obviously critical. Healthy patient studies in biosimilar development are more efficient and have been the clinical development standard thus far. Phase 1 studies in healthy patients have been carried out for biosimilars of trastuzumab and bevacizumab because “you can justify the benefit-risk ratio with that particular trial design for those molecules because they target tumor types,” Baker explained.
However, there is now an ongoing debate amongst oncologists, pharmacologists, and regulators about whether you can safely do a single-dose study in healthy volunteers with immuno-oncology agents coming off patent now, like the check-point inhibitors. “Because these treatments target the immune system, there are some serious side-effects you may have to consider,” Meyer added. “Healthy volunteers obviously don’t have tumors, but everyone has an immune system.”
Baker and Meyer expect there will be more discussion amongst biosimilar development clinical professionals and regulators moving forward on this topic. As there is no precedent for how to handle Phase 1 trials for some of these agents, there will likely need to be some sort of consensus amongst regulators moving forward.
“We may find the answer is yes, we can do Phase 1 studies in healthy volunteers for check-point inhibitors,” Baker concluded. “But we need to get regulators input. There’s just no precedent established yet.”