Over the past year, the biosimilar industry has developed two mantras: “education, education, education,” and “strategy, strategy, strategy.” Without a doubt, education and strategy will significantly influence the uptake of biosimilars and benefit the companies that make them.
But after my conversation with HoUng Kim, the head of the strategy and operations division for Celltrion Healthcare, I’d like to add another mantra to this list: “data, data, data.”
In my list of the top five biosimilar developments in 2016, I homed in on the release of the highly anticipated NOR-SWITCH data, which demonstrated the safety and efficacy of a single switch from Remicade to Celltrion’s Remsima in six indications. Among NOR-SWITCH and a number of other studies emphasizing biosimilars’ reliability, we are clearly entering the age of real-world evidence (RWE).
Throughout my conversation with Celltrion’s Kim, we continued to arrive back at the importance of generating and being transparent with biosimilar data — not just for the benefit of patients and physicians, but also for the biosimilar company. As the global market for biosimilars grows more competitive, companies will need a strategy (cue mantra #2) to make their candidates stand out in the market. And being vigilant about the distribution of your data is one way to differentiate your products.
Fear-mongering about the safety and long-term performance of biosimilars continues to challenge the biosimilar industry. But Kim emphasizes Celltrion’s goals to meet this challenge head-on through the generation, publication, and distribution of data.
“We believe it’s best to focus on publishing data and providing all stakeholders with the appropriate information to battle the claims and warnings they’re encountering today,” Kim says. “Physicians, patients, and payers need to base their choices on objective evidence. We are committed to opening up the data we currently have and are willing to generate further data should any stakeholder need to see more.”
Celltrion’s Biosimilar Journey
As the creator of Remsima (infliximab), the first monoclonal antibody (mAb) biosimilar to be approved in Europe in 2013, Celltrion is a leading player shaping the global biosimilar market today.
Celltrion originally launched in 2002 as a CMO. During that time, the company gained its footing in the manufacturing space. It completed its first manufacturing facility in 2005 and signed a supply agreement for Orencia with Bristol-Myers Squibb. In the following years, the company began making necessary investments to build up its infrastructure for R&D and clinical and regulatory affairs, and its sales force. The company’s ultimate goal was to boost capabilities to create new biologics in the infectious disease, immunology, and oncology spaces, as well as biobetters.
It wasn’t until 2008, after building up its manufacturing and technological resources, that Celltrion announced the launch of its biosimilar business. But, as a statement on the company’s website describes, entering the biologics and biosimilar space meant venturing down a lonely path for the company.
“During our initial period of biosimilar development, the European Medicines Agency [EMA] was the only leading agency that had published biosimilar guidelines,” Kim explains. “There were also analysts and consultants [along with prominent originator companies] who were predicting an unfavorable future for biosimilars. So, we had a long series of discussions with key opinion leaders in order to weigh these predictions and concerns.”
Ultimately, the company felt biosimilars offered the biggest opportunity. Indeed, Kim referenced the allure of becoming the first company to launch a mAb biosimilar. “We began to focus on making our product the first biosimilar in the market,” Kim says.
“Data, Data, Data:” Establishing Stakeholder Trust
In 2012, Celltrion’s Remsima received approval from the Ministry of Food and Drug Safety (MFDS) in South Korea, which established biosimilar regulatory legislation in 2009. A year later, the infliximab biosimilar earned a nod from the EMA.
When I asked how the first biosimilar was received in South Korea, Kim described many of the difficulties the U.S. is facing today in terms of physician and patient caution. He explains, “In South Korea when Remsima was approved, there was no reference information other than the biosimilar clinical trials. So it took some time to get the buy-in from patients, physicians, and payers.”
The U.S., on the other hand, has had upwards of 10-years-worth of data on the EU’s biosimilar experience and product-specific clinical data to help physicians and patients understand biosimilars.
“When it came time for the approval of Inflectra in the U.S., we had more than 8,000 published cases of infliximab biosimilar use,” Kim offers.
We learned earlier this year, thanks to a survey of biologics-prescribing U.S. physicians, that peer-reviewed medical journals are the most trusted source of information for physicians. Those same physicians also have expressed an interest in reviewing switching data.
Kim emphasizes the importance of granting stakeholders access to data such as these. One of the ways this can be accomplished is by translating data into layman’s terms to help patients and payers understand what biosimilars are and to overcome any negative claims about their performance.
Similarly, Celltrion’s pursuit of publication in medical journals has helped provide a sense of what physicians in the medical community need from a data standpoint.
“Even though the clinical data had been accepted by the regulatory agency, there was still another step to validate the data,” Kim explains. “We still needed to submit the data to board members or editors of medical journals. These are leading physicians who approach the data from the medical perspective.”
In one situation, journal editors asked to see additional statistical analysis in different populations in Celltrion’s pivotal equivalence studies between the biosimilar infliximab and Remicade. Applying these additional validations to the data packages for the PLANETRA (Phase 3) and PLANETAS (Phase 1) studies helped secure publications in a popular Rheumatology journal, Annals of the Rheumatic Diseases (ARD).
“To be published is to receive validation from the medical society,” he said. “Obviously, this helps build trust and familiarity amongst physicians and, ultimately, patients.”
However, the necessity of receiving this validation was not something the company originally thought about during its development of Remsima. Instead, its primary goal was to meet regulatory requirements. But when it came time to launch the biosimilar, there were many misunderstandings about what biosimilars are.
“When it came time to launch, we discovered there was an elevated misunderstanding of biosimilars amongst patients, healthcare professionals, and even in the industry itself,” Kim recalls. In fact, he says recognizing this imbalance of information amongst stakeholders was the company’s biggest lesson moving beyond its first biosimilar approval.
“We didn’t initially consider this situation starting out in biosimilars,” he offers. “We now know that making a diligent effort to share evidence and data is a key factor that could increase the level of biosimilar uptake.”
The Challenges Of Global Development
I’ve written several articles about scientific alignment amongst the major regulators, including the FDA, Health Canada, and the EMA. Though biosimilar guidances from each of these agencies are all quite similar, the agencies occasionally differ in their interpretations of the guidances. Celltrion’s approvals of Remsima/Inflectra in South Korea, the EU, the U.S., and Canada, among other countries, provide good glimpses into what the different regulators emphasized most in their biosimilar reviews.
Arguably, the most noticeable difference was Health Canada’s original decision to hold off approving Inflectra for gastroenterology indications. Kim emphasized the agency’s initial discomfort extrapolating the biosimilar without clinical data in inflammatory bowel disorder (IBD). This was, originally, in stark contrast to the EMA, which believed if a company was using advanced technology to detect any potential differences in the mechanism of action, extrapolation was justifiable. It took further communication between the regulatory agencies to sway Health Canada into adopting a similar position on extrapolation as the EMA and the FDA.
In addition, the company faced requests from Japanese regulators for data from the indigenous population.
One of the bigger regulatory hang-ups Celltrion faced when working with the MFDS and EMA was in selecting the comparator biologic. As Kim describes, the MFDS wanted the reference product to be purchased within Korean territory, while the EMA (at the time) was asking for a comparator purchased from within the EU. (The EMA has since changed its stance and allows companies to source a product from outside the EU).
After producing certification to prove the Remicade distributed within Korea was produced in Europe, the MFDS, permitted Celltrion to use the reference product sourced from the EU.
But in order to use the EU comparator for approval in the U.S., Celltrion needed to provide additional data. The FDA particularly stressed thorough statistical testing to demonstrate molecular-level comparability and pharmacological equivalence between the reference products from inside and outside the U.S.
Celltrion’s experiences go to show regulators’ positions can evolve over time. In the end, Kim maintains, “As a drug developer, it’s our job to diligently provide the data to meet each regulator’s requirements.”