SAN DIEGO -- As biosimilar drugs reached the market in the U.S. and Europe, two key questions emerged: do they really save money for patients and/or the healthcare system, and are there risks to patients in switching from an originator biologic drug that has been working well for them to a close-but-not-perfectly-identical copy?
The first question was addressed at length here on Sunday, during a "Great Debate" at the American College of Rheumatology's annual meeting. For the U.S., at least, it was clear that the hoped-for economic savings have not materialized. But the debaters' take on the second question left it unresolved.
Since the debate was held, though, a series of studies touching on the risk question were presented. They add up to one thing: it's a really tough question that so far can't be answered definitively.
Including these additions, the overall body of literature can be divided into two types: double-blind randomized studies conducted by biosimilar manufacturers, and open-label observational studies with prospectively collected data. And their results are not quite the same.
The differences also highlight the controversy that has recently grown up around the supposed gold standard of randomized controlled trials: whether their results deserve more weight than studies using uncontrolled data from less carefully selected patients in regular clinical practice, i.e., the "real world."
Uniformly and unsurprisingly, the manufacturers' trials show no loss of efficacy or increase in adverse events when patients switch from an originator biologic to a biosimilar. (If they didn't, they couldn't claim biosimilarity.) , sponsored by Boehringer Ingelheim, randomized 295 patients stable on the original adalimumab (Humira) either to remain on the drug or to switch to the firm's biosimilar Cyltezo. Efficacy was maintained in nearly all patients, with no difference between groups, and rates of discontinuation in this phase were very similar.
But a number of "real-world" studies have been conducted in Europe, where national health system payers have ordered many patients to switch over for reasons of cost. (In these countries, biosimilars genuinely cost less.) In these studies, a minority of patients -- usually around 10% -- either lose efficacy or show new adverse events and discontinue the biosimilar.
Some examples from the studies of rheumatology biologics reported here:
- 60 of 635 (Enbrel) to biosimilar Benepali discontinued within 6 months, in about equal numbers for loss of efficacy and adverse events (study funded by Biogen, maker of Benepali)
- 11 of 89 to Benepali while in remission later discontinued
- 295 of 1,621 discontinued Benepali within 1 year after switching from Enbrel (although the same registry showed 142 discontinuations among 440 remaining on Enbrel during the same time period)
- 691 (Remicade) to biosimilars (Benepali, Inflectra, Remsima), of whom 5%-28% discontinued
One obvious source of the disconnect is that the European studies all involved patients who knew they were switching from their familiar drug -- most had been taking it for years -- to the biosimilar, and in some cases the switch was mandatory. In contrast, the manufacturers' studies were blinded and participants didn't know if they had switched.
During the Sunday debate, the "pro-switch" speaker, Jonathan Kay, MD, of the University of Massachusetts Medical School in Worcester, noted that painful and swollen joint counts illustrate the disconnect. Patients complaining of inefficacy after switching will often show increases in painful joints -- a patient self-reported measure. But rarely is this confirmed in swollen joint counts, which are more objective in that they are made by the treating physician.
Knowledge of having made the switch is the difference, said Alfons den Broeder, MD, PhD, senior author of the Dutch study, of Sint Maartenskliniek in Nijmegen. Loss of efficacy "only pops up in unblinded [studies]," he told 鶹ý.
Is this a "nocebo" effect, as Kay argued during the debate? That's hard to prove and just as hard to disprove, researchers here said. The drug molecules do differ; individuals' responses to a given biologic drug vary for both efficacy and adverse events, and patient-specific interactions with subtle features of the drug such as glycosylation patterns may be the reason.
And in some cases, actual disease worsening following drug switching can't be denied. Kim Hørslev-Petersen, MD, of the University of Southern Denmark in Odense, noted that one patient on Benepali for 3 months showed a host of new symptoms, including MRI-verified spinal inflammation, that all resolved when he went back to Enbrel.
But den Broeder said that problems appear more likely when patients are made to switch against their will. Hørslev-Petersen concurred, saying that "shared decision-making" should be the goal in considering switches to biosimilars.