By Anna Rose Welch, Director, Cell & Gene Collaborative
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It’s not often that I get the opportunity to discuss biosimilar clinical trials; in fact, despite the fact that almost all the biosimilars currently marketed have undergone large comparative efficacy studies, the topic is rarely discussed at industry events or in scholarly publications. If clinical trials do come up, the discussion tends to vacillate between two extremes: one, that companies (especially in the early biosimilar days) have gone above and beyond in providing additional clinical data regardless of whether regulators have asked for it; or two, it’s time to say goodbye to comparative efficacy studies in biosimilar development because they’re not nearly as sensitive as comparative analytics.
In the past year or so, there have been several great publications put forth proposing methods of reshaping the biosimilar development paradigm to place less emphasis on large and expensive comparative efficacy studies. Though the most recent of these publications has compiled much of the necessary data to advance discussions with regulators in this area, transitioning the development protocol for biosimilar development will likely take a handful of years. In the meantime, companies seeking approval for biosimilars — especially the more complex mAbs in rheumatology and oncology — will need to provide comparative efficacy data. Though it’s rarely discussed, I fail to believe that these trials are a cut-and-dried effort, even for companies that have undergone clinical development of novel biologics or other biosimilars. (Heavens knows nothing else has been a straightforward walk in the park for this industry!)
At the U.S. World Biosimilar Congress (WBC), one of the presentations I was most looking forward to was delivered by two experts from Covance on strategies that biosimilar makers could employ to make their clinical trials stand out from the crowd. (For a good example of this, look no further than Celltrion’s PANTS study…for obvious reasons.) In this first of what will be two articles, I breakdown the main points from Covance executive director Joan Meyer’s presentation about the biggest clinical challenges and considerations facing biosimilar companies today.
The Biggest Biosimilar Clinical Trial Challenges
Today, we spend a lot of time discussing how biosimilars — especially those with multiple competitors per reference product — can differentiate to add value and best compete. However, as the market for certain reference products grows increasingly crowded with biosimilar competitors, there is an increasing need for creativity on the clinical trial side, as well. As Meyer spelled out during her presentation, biosimilars are obviously competing against novel treatments to recruit patients in the same therapeutic indications. But competition amongst biosimilar makers for patients is something fierce, as well.
To put this into perspective, consider the fact that there are five Herceptin biosimilars currently launched in the U.S., each of which boasts its own large comparative efficacy study. Looking at the supplementary materials compiled for a recent publication, on average, there were anywhere from 500 to 1,000 patients enrolled in biosimilar comparative efficacy studies for each approved rheumatology and oncology biosimilar (not including filgrastim or pegfilgrastim). One trial for a Humira biosimilar enrolled upwards of 1,300 patients (!!).
In addition to competition for recruitment, finding an investigator willing to devote their efforts to biosimilar comparative efficacy studies can also be a challenge. Given the innovative new medicines coming to market, especially in the oncology and cell and gene space, many clinical investigators are drawn to the treatment options that could potentially revolutionize their therapeutic area. While many of these investigators’ professional societies have included biosimilars in their treatment guidelines today, it’s still rare that biosimilars enter the limelight of the plenary sessions at these organizations’ annual conferences.
Ensuring that you’re working with sites that have expressed willingness and interest in working on biosimilar clinical trials is necessary to ensure there will be follow-through and engagement on both the investigator and site level. But this is easier said than done. As an article by the U.K.’s National Institute of Health Research (NIHR) explained, while many companies may feel they have a sufficient list of KOLs and willing sites to participate in their biosimilar studies, this has not often been the case. NIHR has observed that, when it came time to recruit sites and investigators for biosimilar studies, many companies provided lists of “usual suspects,” or sites in locations that are typically high demand, have high investigator turnover, and have limited bandwidth. In turn, these lists proved unhelpful from a site and investigator selection standpoint.
The Benefit Of Biosimilar Clinical Trials
Though biosimilar treatments may not be a shiny new innovative drug, Meyer pointed out a few benefits biosimilar clinical trials do provide for investigators and patients.
For one, comparative efficacy studies are not like those typically carried out for novel drugs; as such investigators likely will not (nor should they) encounter significant or unusual adverse events during the course of the study. This is all thanks to the wealth of clinical data from the reference product and real-world biosimilar usage overseas. Because of this, Meyer said physicians are much more informed going into the trial about what clinical efficacy will look like for the patient compared to a new drug which can be a blank slate.
Because these are not typical Phase 3 studies, the lack of a placebo arm is also a benefit for patients and investigators — especially in regions where biologics access may be limited. In a traditional Phase 3 trial for a novel treatment, patients are often concerned about being placed in the placebo arm because they won’t even be receiving the treatment, Meyer explained. But for a biosimilar study, patients are either receiving the standard of care or an equal version of that standard of care. Not only does this mean that patients are actually receiving treatment, regardless of the arm in which they’re placed, but this can also be a huge boon for patients located in countries that have not had reliable biologics coverage.
“In your country selection strategy, it’s important to consider the reimbursement strategy,” Meyer said. “A biosimilar clinical trial could be a really attractive study for both the patients and their physicians because they can now treat their patients using these very expensive compounds that perhaps were not previously available.”
The Biggest Key To Success: Keeping It Simple For Patients
As is the case for any clinical trial — biosimilar or novel treatment — we are in the age of patient centricity, meaning its more important than ever to make participation in a clinical trial a simple and comfortable affair for the patient. This includes keeping a close eye on logistics — in particular where the majority of your patient population is located in regard to the trial site. It can be an interesting geography lesson when searching for patient populations around the U.S., Meyers pointed out. It’s common to find a large number of patients for a variety of diseases in New York, New Jersey, Florida, and LA. But the occasional city may pop up and surprise you, she said; for instance, when looking for RA patients, it just so happens that there’s a large patient population in St. Louis, Missouri.
How often patients need to return for treatment or follow-up testing is another big logistical consideration. Meyer explained, “We have found time and time again that patients are willing to undergo two procedures at a doctor’s visit. You hit three, and their desire to be in a clinical study decreases.” This also applies to the amount of times patients will need to return to their doctors’ offices, which is made more difficult should the patient not live close to the clinical trial site. On average, patients are willing to drive up to 30 miles to participate in a trial, Meyers added. Of course, this will also differ depending on the region and the therapeutic indication. Driving 30 miles may mean something different for an RA patient than it would for patients with idiopathic pulmonary fibrosis, for example, depending upon the current standards of care, overall treatment access, and the prevalence of clinical trial opportunities in the specific indication. Geographically, as well, 30 miles may be more or less manageable in the U.S. compared to those living in, say, Brazil, or certain areas in Europe.
In light of current Covid-19 challenges, there are a number of opportunities rapidly unfolding in the clinical space that could only add value to the clinical trial process. As my colleague over at Clinical Leader has written in numerous articles, this pandemic may be the key to making virtual clinical trials, home administration, and remote visits part of the future norm. Meyer suggested that virtual trials in particular can be used to improve the convenience for patients enrolled in biosimilar clinical trials — for example, enabling patients to go to their local chain pharmacy to have samples collected.
There could also be opportunities to train physicians to become independent clinical trial investigators at a hospital site closer to the patients. Meyer pointed to TransCelerate’s clinical study training modules. Programs such as these have proven valuable in appointing physicians to be local investigators in cases where the patient population may be too widespread to converge upon a set system of sites (i.e., rare disease). “You have to go where the patients are,” Meyer added. This will be exceptionally important to keep in mind as the biosimilar development pipeline shifts away from large population blockbuster treatments like Humira to smaller patient population treatments.
Stay tuned for a follow-up conversation with Meyer and her colleague Alicia Baker from The Covance Biosimilar Center for Excellence. Meyer and Baker will share the trends and opportunities they’re seeing in the biosimilar clinical sphere.