Equivalence of Generic Glatiramer Acetate in Multiple Sclerosis

Abstract

for the Glatiramer Acetate Clinical Trial to Assess Equivalence With Copaxone (GATE) Study Group IMPORTANCE The patents for the first approved treatments for relapsing-remitting multiple sclerosis are expiring, creating the opportunity to develop generic alternatives.OBJECTIVE To evaluate in the Glatiramer Acetate Clinical Trial to Assess Equivalence With Copaxone (GATE) study whether generic glatiramer acetate (hereafter generic drug) is equivalent to the originator brand glatiramer acetate (hereafter brand drug) product, as measured by imaging and clinical end points, safety, and tolerability. DESIGN, SETTING, AND PARTICIPANTS Randomized, multicenter, double-blind, active and placebo-controlled phase 3 trial. The setting included academic medical centers and clinical practices. Participants were patients with relapsing-remitting multiple sclerosis 18 to 55 years old with at least 1 relapse in the prior year and 1 to 15 gadolinium-enhancing brain magnetic resonance imaging lesions. They were randomized between December 7, 2011, and March 21, 2013. The last participant completed follow-up December 2, 2013.INTERVENTIONS Participants were randomized 4.3:4.3:1 to receive generic glatiramer acetate (20 mg), brand glatiramer acetate (20 mg), or placebo by daily subcutaneous injection for 9 months. MAIN OUTCOMES AND MEASURESThe primary end point was the total number of gadolinium-enhancing lesions during months 7, 8, and 9. Additional end points included other magnetic resonance imaging parameters, annualized relapse rate, and Expanded Disability Status Scale score. Safety and tolerability were assessed by monitoring adverse events, injection site reactions, and laboratory test results. RESULTSIn total, 794 participants were randomized and treated with generic drug (n = 353), brand drug (n = 357), or placebo (n = 84). The estimated mean numbers of gadolinium-enhancing lesions with generic drug and brand drug were lower than with placebo (ratio, 0.488; 95% CI, 0.365-0.651; P < .001), confirming study sensitivity. For gadolinium-enhancing lesions, the estimated ratio of generic drug to brand drug was 1.095 (95% CI, 0.883-1.360), which was within the predefined equivalence margin of 0.727 to 1.375. The incidence, spectrum, and severity of reported adverse events, including injection site reactions, were similar in the generic drug and brand drug groups. CONCLUSIONS AND RELEVANCEAs treatment for relapsing-remitting multiple sclerosis, glatiramer acetate generic drug and brand drug had equivalent efficacy, safety, and tolerability.TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01489254

Clinical effectiveness and cost-effectiveness of beta-interferon and glatiramer acetate for treating multiple sclerosis: systematic review and economic evaluation

“…[174][175][186][187][188][189][190][191][192][195][196][197][198][199][200]213,216,[219][220][222][223][224] Studies that reported methods of allocation concealment (the concealment of study allocation before the beginning of assigned treatment) were also judged to be at low risk of bias (n = 22/35), 171,[174][175]181,[188][189][190][191][195][196][198][199]207,213,[216][217][219][220][221][222][223][224] with the exception of one study that used open allocation. 170 All studies citing central allocation were judged as having a low risk of bias.…”

“…170 All studies citing central allocation were judged as having a low risk of bias. 171,175,190,198,207,213,[216][217][219][220]222 Risk in methods of blinding…”

“…[170][171][172][174][175][181][182][183][184][185][186]188,190,192,[195][196][197][198][199]209,211,213,[216][217][219][220][221][222][223][224] Fourteen studies, most of which were comparisons between different active drugs, specifically did not blind participants or practitioners; 170,[182][183][184][185][186]188,190,192,[195][196][197]199,216 in another 15 studies, participants were initially blinded but were at high risk of unblinding from increased rates of side effects. [171][172][174][175]…”

“…170,[182][183][184][185][186]188,190,192,[195][196][197][198][199]216 All studies that reported MRI outcomes and detailed methods for blinding of MRI assessment were found to be at low risk of bias (n = 13/15). [171][172]184,188,196,[199][200]209,213,216,[219][220][221] Risk in data analysis and reporting…”

“…173,181,183,186,191,200,209,213,216,223 In 17% (n = 6/35) of studies, outcomes were not reported as stated, and these were designated to be at high risk of bias from selective reporting. 173,181,188,[198][199]207 Finally, all studies funded by drug manufacturers were designated as being at high risk of bias under the 'other' category, [171][172][173]175,[183][184]186,[189][190]192,195,[197][198][199][200]207,209,213,216,[219][220][221][222][223][224] as this was not covered by other questions in the Cochrane risk of bias tool. …”