Systematic Literature Review Shows Low Risk of Safety Concerns or Loss of Efficacy After Switching to a Biosimilar

March 5, 2018

In an effort to evaluate whether switching from a reference biologic to a biosimilar could lead to altered clinical outcomes—such as enhanced immunogenicity, compromised safety, or reduced efficacy—a research team, led by Hillel Cohen, PhD, conducted a systematic literature review of all available switching studies.

Despite the fact that no new safety or efficacy concerns have been detected in more than 10 years and 700 million patient days of experience with biosimilar medicines, some stakeholders remain cautious about switching from reference products to biosimilars, as they fear that such a switch could result in serious problems.

In an effort to evaluate whether switching from a reference biologic to a biosimilar could lead to altered clinical outcomes—such as enhanced immunogenicity, compromised safety, or reduced efficacy—a research team, led by Hillel Cohen, PhD, conducted a systematic literature review of all available switching studies.

The researchers searched Medline and Embase databases for switching studies up to June 30, 2017. Publications were considered if they contained efficacy or safety information on a switch from a reference drug to a biosimilar (studies that considered switches from erythropoietin to darbepoetin, erythropoietin to pegylated-erythropoietin, and insulin to insulin were not included).

In total, the researchers arrived at 90 studies that enrolled 14,225 unique individuals and that contained primary switching data. The studies included 7 molecular entities used to treat 17 disease indications. Most studies enrolled between 30 and 60 subjects.

Safety, Efficacy, and Immunogenicity

Thirty-six publications provided primary data describing the efficacy of large biologics (those with proteins 200 amino acids in length or larger, including etanercept, adalimumab, infliximab, and rituximab) after switching to biosimilars.

Among these publications, 12 were single-arm studies describing patients whose treatment was switched, and 24 were cohort studies comparing patients who switched with patients who did not. “Sporadic observations of loss of responses were reported in a few studies,” say the authors, though consistent patterns were observed.

Of switching articles examined, 39 reported treatment-emergent adverse events (TEAEs) and serious TEAEs. In 32% of these, serious TEAEs were reported as “nil” or 0%.

Anti-drug antibodies (ADAs) were assessed in 24 studies considering larger biosimilars, and 7 provided information on neutralizing antibodies (NABs). Thirteen studies assessed ADAs—4 addressed NABs—among the smaller biosimilars (erythropoietin, filgrastim, human growth hormone). “In all studies reporting immunogenicity data, ADA and NAB levels were found to be comparable at baseline and at the end of study across all disease indications and treatment groups,” say the authors.

One report raised safety concerns after switching from reference infliximab to a biosimilar; a study reviewing a Turkish claims database showed an 82% dropout rate (among 148 switched patients) versus a 24% dropout rate in a control group who remained on the reference product. The authors state that it is possible that these were chance results.

The authors further break down evidence from biosimilar switching studies by indication:

Inflammatory Arthritis

Regulatory approval for CT-P13, an infliximab biosimilar (marketed in the United States as Inflectra and in the European Union as Remsima) was supported by 2 randomized clinical trials—the first a phase 1 study in ankylosing spondylitis and the second a phase 3 study in rheumatoid arthritis (RA)—each incorporating switching and at least 1 year of follow-up. There were no clinically meaningful differences in safety or immunogenicity observed among patients who switched or did not switch in either trial.

Approval of SB2 (marketed as Renflexis) was supported by a phase 3 study in 584 patients with RA, in which patients were randomized to receive either SB2 or the reference infliximab. At week 54, patients receiving the reference were switched to SB2 and followed to week 78. No changes were detected in safety or efficacy.

The ongoing DANBIO study, a Danish registry study of 802 patients with RA, psoriatic arthritis, and axial spondylitis who switched to CT-P13, has observed a dropout rate of 16%, “comparable to the rate observed with historical controls of the reference medicine.”

Inflammatory Bowel Disease

While the NOR-SWITCH study provided data showing no significant difference in efficacy, safety, and immunogenicity in patients with inflammatory bowel disease (IBD) who switched to biosimilars versus those who remained on reference drugs, randomized clinical trials in IBD are fewer in number.

Cohort studies have provided switching data, however; in a prospective, multi-center cohort study of CTP-P13 in patients with Crohn disease and ulcerative colitis who were switched from reference infliximab to the biosimilar, “The authors evaluated effectiveness and safety parameters and reported outcomes comparable to previous experience with reference infliximab.”


Five switching studies considered psoriasis, including a phase 3 study conducted to support approval of GP2015, (a biosimilar etanercept that will eventually be marketed in the United States as Erelzi). This study included 3 switches and found that the safety, efficacy, and immunogenicity profiles of the switched and non-switched arms were similar.

A phase 3 study of ABP-501 (a biosimilar adalimumab that will eventually be marketed as Amjevita in the United States and as Amgevita in the European Union) also addressed psoriasis. In the study of 347 patients treated with either the biosimilar or the reference adalimumab, patients who switched to the biosimilar at week 16 showed no increase in AEs or the incidence of ADAs up to week 52.

Switching Smaller Biologics

Nineteen studies provided efficacy data after switching from reference medicines to biosimilars of smaller biologics.

Efficacy results were similar in all erythropoietin studies, with the most common efficacy endpoint being a change in hemoglobin levels over time.

Two switching studies of filgrastim were identified, with changes in absolute neutrophil count and incidence of febrile neutropenia serving as efficacy endpoints. One of the studies incorporated 5 separate switching events, and patients who switched showed no differences in safety or efficacy from those who did not. No NABs were detected in any of the patients in either study arm.

Human growth hormones had 9 switching studies available, and comparable efficacy and safety were seen after in the 7 studies that provided efficacy and safety data.

Switching in Healthy Volunteers

In all 10 switching studies of filgrastim, erythropoietin, and human growth hormone involving healthy volunteers, safety profiles of individuals who received reference biologics followed by biosimilars were similar to safety profiles of those who remained on reference products.

Multiple Switches

As of June 2017, 3 multiple switch studies had been published, 1 of each considering filgrastim (discussed above), etanercept (also discussed above), and adalimumab biosimilars.

The switching study considering GP2017, a proposed adalimumab biosimilar for which Sandoz filed a Biologics License Application with the FDA in January 2018, was published after the cut-off date of the review, but used a 4-switch study design in patients with moderate to severe chronic plaque psoriasis. Efficacy, AEs, and immunogenicity were similar for the proposed biosimilar and the reference at week 51.

The authors concluded that the large body of published evidence on switching from a reference biologic to a biosimilar does not show significant difference in ADAs or NABs in patients who switched to a biosimilar compared to patients who did not switch, and that there were no reported increases in treatment-related safety events—including loss of efficacy—related to switching.

“Thus, the extensive data collected to date suggest that the act of switching from a reference medicine to a biosimilar is not inherently dangerous, and that patients, healthcare professionals, and the public should not assume that it is problematic,” say the authors.


Cohen HP, Blauvelt A, Rifkin RM, Danese S, Gokhale SB, Woollett G. Switching reference medicines to biosimilars: a systematic literature review of clinical outcomes. [Published online March 3, 2018] Drugs. doi: 10.1007/s40265-018-0881-y.