[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.163.129.96. Please contact the publisher to request reinstatement.
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Download PDF
Figure 1.
Consolidated Standards of Reporting Trials Diagram of Enrollment and Follow-up of Study Patients
Consolidated Standards of Reporting Trials Diagram of Enrollment and Follow-up of Study Patients

aSome patients discontinued using the study drug and subsequently discontinued follow-up in the study.

Figure 2.
Primary Study End Point (Full Analysis Set)
Primary Study End Point (Full Analysis Set)

A, Data are the estimated means as calculated from the study sensitivity analysis that included all 3 treatment groups. B, To estimate the ratio of generic drug to brand drug, the analysis included the generic glatiramer acetate and brand glatiramer acetate treatment groups.
aThe estimated mean number of new and persisting gadolinium-enhancing lesions during months 7 through 9 for the combined generic glatiramer acetate and brand glatiramer acetate treatment groups was 0.40.

Table 1.  
Baseline Characteristics (Full Analysis Set)
Baseline Characteristics (Full Analysis Set)
Table 2.  
Magnetic Resonance Imaging and Clinical End Points (Full Analysis Set)a
Magnetic Resonance Imaging and Clinical End Points (Full Analysis Set)a
Table 3.  
Adverse Events (Safety Population)
Adverse Events (Safety Population)
1.
Racke  MK, Lovett-Racke  AE, Karandikar  NJ.  The mechanism of action of glatiramer acetate treatment in multiple sclerosis. Neurology. 2010;74(suppl 1):S25-S30.
PubMedArticle
2.
Bornstein  MB, Miller  A, Slagle  S,  et al.  A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N Engl J Med. 1987;317(7):408-414.
PubMedArticle
3.
Johnson  KP, Brooks  BR, Cohen  JA,  et al; Copolymer 1 Multiple Sclerosis Study Group.  Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. Neurology. 1995;45(7):1268-1276.
PubMedArticle
4.
Comi  G, Filippi  M, Wolinsky  JS; European/Canadian Glatiramer Acetate Study Group.  European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging–measured disease activity and burden in patients with relapsing multiple sclerosis. Ann Neurol. 2001;49(3):290-297.
PubMedArticle
5.
Comi  G, Martinelli  V, Rodegher  M,  et al; PreCISe Study Group.  Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial [published correction appears in Lancet. 2010;375(9724):1436]. Lancet. 2009;374(9700):1503-1511.
PubMedArticle
6.
Mikol  DD, Barkhof  F, Chang  P,  et al; REGARD Study Group.  Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the Rebif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol. 2008;7(10):903-914.
PubMedArticle
7.
Cadavid  D, Wolansky  LJ, Skurnick  J,  et al.  Efficacy of treatment of MS with IFNβ-1b or glatiramer acetate by monthly brain MRI in the BECOME study. Neurology. 2009;72(23):1976-1983.
PubMedArticle
8.
O’Connor  P, Filippi  M, Arnason  B,  et al; BEYOND Study Group.  250 µg or 500 µg Interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study [published corrections appear in Lancet Neurol. 2011;10(2):115, 2009;8(11):981, and 2012;11(1):27].  Lancet Neurol. 2009;8(10):889-897.
PubMedArticle
9.
Comi  G, Cohen  JA, Arnold  DL, Wynn  D, Filippi  M; FORTE Study Group.  Phase III dose-comparison study of glatiramer acetate for multiple sclerosis. Ann Neurol. 2011;69(1):75-82.
PubMedArticle
10.
Fox  RJ, Miller  DH, Phillips  JT,  et al; CONFIRM Study Investigators.  Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis [published correction appears in N Engl J Med. 2012;367(17):1673]. N Engl J Med. 2012;367(12):1087-1097.
PubMedArticle
11.
Lublin  FD, Cofield  SS, Cutter  GR,  et al; CombiRx Investigators.  Randomized study combining interferon and glatiramer acetate in multiple sclerosis. Ann Neurol. 2013;73(3):327-340.
PubMedArticle
12.
Ford  C, Goodman  AD, Johnson  K,  et al.  Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: results from the 15-year analysis of the US prospective open-label study of glatiramer acetate. Mult Scler. 2010;16(3):342-350.
PubMedArticle
13.
Hartung  DM, Bourdette  DN, Ahmed  SM, Whitham  RH.  The cost of multiple sclerosis drugs in the US and the pharmaceutical industry: too big to fail? Neurology. 2015;84(21):2185-2192.
PubMedArticle
14.
Hauser  SL, Johnston  SC.  Multiple sclerosis drugs: sticker shock. Ann Neurol. 2012;71(5):A5-A6.
PubMedArticle
15.
Woodcock  J, Griffin  J, Behrman  R,  et al.  The FDA’s assessment of follow-on protein products: a historical perspective. Nat Rev Drug Discov. 2007;6(6):437-442.
PubMedArticle
16.
Reingold  SC, Steiner  JP, Polman  CH,  et al.  The challenge of follow-on biologics for treatment of multiple sclerosis. Neurology. 2009;73(7):552-559.
PubMedArticle
17.
Schellekens  H, Klinger  E, Mühlebach  S, Brin  JF, Storm  G, Crommelin  DJ.  The therapeutic equivalence of complex drugs. Regul Toxicol Pharmacol. 2011;59(1):176-183.
PubMedArticle
18.
Mühlebach  S, Vulto  A, de Vlieger  JS, Weinstein  V, Flühmann  B, Shah  VP.  The authorization of non-biological complex drugs (NBCDs) follow-on versions: specific regulatory and interchangeability rules ahead? GaBi J. 2013;2(4):204-207. doi:10.5639/gabij.2013.0204.054.Article
19.
Schellekens  H, Stegemann  S, Weinstein  V,  et al.  How to regulate nonbiological complex drugs (NBCD) and their follow-on versions: points to consider. AAPS J. 2014;16(1):15-21.
PubMedArticle
20.
Ventola  CL.  Biosimilars, part 1: proposed regulatory criteria for FDA approval. P T. 2013;38(5):270-287.
PubMed
21.
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonised tripartite guideline: guideline for good clinical practice: E6(R1). Current step 4 version dated June 10, 1996. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf. Accessed September 28, 2014.
22.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053.
PubMedArticle
23.
Polman  CH, Reingold  SC, Banwell  B,  et al.  Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302.
PubMedArticle
24.
Kurtzke  JF.  Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology. 1983;33(11):1444-1452.
PubMedArticle
25.
Anderson  G, Meyer  D, Herrman  CE,  et al.  Tolerability and safety of novel half milliliter formulation of glatiramer acetate for subcutaneous injection: an open-label, multicenter, randomized comparative study. J Neurol. 2010;257(11):1917-1923.
PubMedArticle
26.
Havrdova  E, Galetta  S, Hutchinson  M,  et al.  Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study. Lancet Neurol. 2009;8(3):254-260.
PubMedArticle
27.
Oberye  J, van den Tweel  E, Mulder  M, Voortman  G, Hooftman  L.  Randomised, double-blind, cross-over trial of GTR (generic glatiramer acetate) in healthy volunteers shows similar tolerability and safety to Copaxone (P477) [abstract]. J Neurol. 2012;259(suppl 1):S113. doi:10.1007/s00415-012-6524-4.
28.
US Food and Drug Administration. FDA approves first generic Copaxone to treat multiple sclerosis. For immiediate release April 15, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm443143.htm. Accessed September 7, 2015.
29.
Citizen petition denial letter from CDER to Teva Pharmaceuticals. Date posted April 16, 2015. http://www.regulations.gov/#!documentDetail;D=FDA-2015-P-1050-0012. Accessed September 7, 2015.
30.
European Medicines Agency. Guideline on similar biological medicinal products containing interferon beta. Adopted December 15, 2011. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/01/WC500120652.pdf. Accessed September 1, 2015.
31.
Sormani  MP, Bonzano  L, Roccatagliata  L, Cutter  GR, Mancardi  GL, Bruzzi  P.  Magnetic resonance imaging as a potential surrogate for relapses in multiple sclerosis: a meta-analytic approach. Ann Neurol. 2009;65(3):268-275.
PubMedArticle
32.
Sormani  MP, Bruzzi  P.  MRI lesions as a surrogate for relapses in multiple sclerosis: a meta-analysis of randomised trials. Lancet Neurol. 2013;12(7):669-676.
PubMedArticle
Original Investigation
Clinical Trial
December 2015

Equivalence of Generic Glatiramer Acetate in Multiple SclerosisA Randomized Clinical Trial

Author Affiliations
  • 1Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, Ohio
  • 2Functional Diagnostics, Research Institute of Traumatology and Orthopedics, Nizhniy Novgorod, Russian Federation
  • 3Neurology Center Lodz, Lodz, Poland
  • 4Lycalis sprl, Brussels, Belgium
  • 5Department of Health Sciences, University of Genoa, Genoa, Italy
  • 6Synthon BV, Nijmegen, the Netherlands
  • 7Image Analysis Center, Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands
JAMA Neurol. 2015;72(12):1433-1441. doi:10.1001/jamaneurol.2015.2154
Abstract

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 Measures  The 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.

Results  In 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 Relevance  As 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

Introduction

Glatiramer acetate is a complex mixture of random polypeptides. Its mechanism of action is not fully elucidated but is postulated to involve effects on adaptive and innate immune mechanisms.1 Double-blind, placebo-controlled trials demonstrated that brand glatiramer acetate (20 mg) administered by daily subcutaneous injection reduces clinical relapses and magnetic resonance imaging (MRI) lesion activity in relapsing-remitting multiple sclerosis (RRMS)24 and the rate of developing clinically definite multiple sclerosis (MS) after a first demyelinating event,5 leading to regulatory approval for these indications. Subsequent clinical trials,611 a 15-year open-label follow-up study,12 and clinical experience support efficacy, safety, and tolerability of brand glatiramer acetate.

Medications are a major and increasing contributor to the high cost of MS care.13 As discussed in a recent editorial,14 although MS drugs represent fewer than 0.1% of prescriptions in the United States, they account for 3.1% of the total drug costs. The patents for the first approved treatments for RRMS (interferon beta and brand glatiramer acetate) are expiring, creating the opportunity to develop generic alternatives, with anticipated cost savings for payers and patients.

Small-molecule generics can be verified as having comparable safety and effectiveness as the innovator drug by showing pharmaceutical equivalence (ie, the same active ingredient, quality, strength, dosage, and route of administration) and bioequivalence (ie, similar rate and extent of absorption). Showing equivalence for biologicals (eg, interferon beta) and complex nonbiological products (eg, brand glatiramer acetate) is more challenging because of their molecular complexity.1519 Extensive in vitro characterization and animal studies are necessary but cannot measure key properties sufficiently to predict in vivo behavior in humans. Moreover, pharmacokinetic assessment for brand glatiramer acetate is not possible, and nonimaging biomarkers relating to efficacy have not, to our knowledge, been validated for any MS therapy to date. Therefore, a clinical trial in the target population is usually necessary for generic biological and complex nonbiological agents.15,20 In this context, we performed the Glatiramer Acetate Clinical Trial to Assess Equivalence With Copaxone (GATE) study to demonstrate that Synthon BV’s 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 in patients with RRMS.

Methods
Study Design

This study was a randomized, multicenter, double-blind, active and placebo-controlled phase 3 clinical trial. Central and local ethics committees approved the study. Participants gave written informed consent before any study-related procedures were performed, and renewal of consent was obtained after the second and each subsequent relapse. The study was conducted in accord with International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use21 guidelines for good clinical practice and principles of the Declaration of Helsinki.22 A study steering committee collaborated with the sponsor (Synthon BV) to design the study and monitor its conduct. An independent data and safety monitoring board reviewed trial conduct and safety data. The data were gathered by the investigators and analyzed by the sponsor. The trial protocol is available in Supplement 2, and additional methodological details are available in the eMethods in Supplement 1.

Participants

We randomized participants from 118 academic medical centers and clinical practices in 17 countries between December 7, 2011, and March 21, 2013. The last participant completed follow-up December 2, 2013. Eligible participants were 18 to 55 years old, had RRMS fulfilling the McDonald23 criteria, an Expanded Disability Status Scale24 (EDSS) score of 0 to 5.5, at least 1 documented relapse in the previous year, and 1 to 15 gadolinium-enhancing lesions on T1-weighted images on screening brain MRI. Screening without a gadolinium-enhancing lesion could be repeated twice, separated by at least 1 month. Key exclusion criteria were clinically significant illness or laboratory abnormalities, as well as prior exposure to brand glatiramer acetate or immunosuppressive treatments. Other MS treatments required discontinuation for varying lengths of time from 1 to 12 months before screening.

Randomization and Masking

Eligible participants were randomized in a 4.3:4.3:1 ratio to receive generic glatiramer acetate (20 mg), brand glatiramer acetate (20 mg), or matching placebo by daily subcutaneous injection for 9 months (Figure 1). Randomization was performed centrally and stratified according to geographical region (European Union, North America, or the rest of the world) and the number of gadolinium-enhancing lesions at screening. Study group assignments were performed using an interactive web and voice response system. At each study site, a treating neurologist supervised medical management. An examining neurologist determined EDSS scores at scheduled and unscheduled visits. During the trial, participants, study personnel, MRI evaluators, steering committee members, and the study statistician (R.M.) were unaware of study group assignments. Participants completing the double-blind study were eligible to receive generic glatiramer acetate in a 15-month open-label extension study.

Procedures

Safety assessments were performed at screening, baseline, and months 1, 3, 6, and 9. The EDSS score was measured at screening, baseline, and months 6 and 9. Standardized brain MRI was performed at screening, baseline, and months 7, 8, and 9 and was analyzed by the Image Analysis Center in Amsterdam, the Netherlands. Two independent, trained, and qualified radiology reviewers and a third reviewer if necessary for adjudication evaluated gadolinium-enhancing lesions in a masked manner. Participants completed a diary for 14 consecutive days at treatment initiation and month 3, recording which of 5 injection site symptoms (pain, itchiness, redness, swelling, or lumps) previously reported for brand glatiramer acetate25 were present.

The primary efficacy end point was the total number of gadolinium-enhancing lesions (ie, the cumulative number of new and persisting gadolinium-enhancing lesions) during months 7 through 9 (based on the European/Canadian Glatiramer Acetate trial4). Other prespecified end points included the following: annualized relapse rate, EDSS score change from baseline to month 9, cumulative combined unique active lesions during months 7 through 9, change in T2-weighted hyperintense lesion number and volume from baseline to month 9, change in nonenhancing T1-weighted hypointense lesion volume from baseline to month 9, percentage change in normalized brain volume from baseline to month 9, and proportion of participants who were free of disease activity at month 9. The number of new gadolinium-enhancing lesions (ie, excluding persisting lesions) during months 7 through 9 was analyzed post hoc.

We defined relapse as new or recurring neurological symptoms, without fever or infection, lasting at least 24 hours and accompanied by new objective neurological findings on the examining neurologist’s evaluation. Sustained EDSS score change was defined as at least a 1.0-point increase from a baseline score of 1.0 or higher or at least a 1.5-point increase from a baseline score of 0, confirmed at 3 months. The combined unique active lesions were new gadolinium-enhancing lesions or new or enlarged T2-weighted hyperintense lesions without double counting. Disease activity free was defined as an absence of the following: relapse, sustained EDSS score change, or new or enlarged T2-weighted hyperintense or gadolinium-enhancing lesions.26 Safety assessments included monitoring of adverse events, local injection site reactions, vital signs, and laboratory test results. Neurological symptoms related to confirmed relapses and local injection site reactions recorded in the tolerability diaries were not additionally reported as adverse events.

Statistical Analysis

Based on the European/Canadian Glatiramer Acetate trial,4 we estimated that the mean number of gadolinium-enhancing lesions during months 7 through 9 would be 1.75 times higher with placebo treatment compared with brand glatiramer acetate treatment. The upper limit of the equivalence margin was set at 1.375, representing 50% of the treatment effect vs placebo observed in the aforementioned trial. The lower limit of the equivalence margin was set at 0.727 to create a symmetrical margin in the log scale. To conclude equivalence between generic glatiramer acetate and brand glatiramer acetate, efficacy in the combined active treatment groups needed to be superior to placebo (confirming study sensitivity), and the 2-sided 95% CI for the estimated ratio of generic drug to brand drug needed to be fully enclosed in the prespecified equivalence margin. Given the sample size as calculated and the estimated width of the 95% CI for the ratio of generic drug to brand drug, the maximal allowable difference between the point estimates to show equivalence would be approximately 10%. With a dropout rate of 12%, we estimated that 336 evaluable participants in each of the generic drug and brand drug groups and 78 evaluable participants in the placebo group would provide 98% power to demonstrate study sensitivity, 92% power to show equivalence of generic drug and brand drug, and 90% power to show study sensitivity and equivalence.

All efficacy and safety analyses were performed using the full analysis set and safety population, respectively (all randomized participants who received ≥1 study drug injection). The primary efficacy analyses were also performed using the per-protocol set, which included all participants who received 80% to 120% of planned study drug administrations in the first 7 months, had at least 1 efficacy assessment during months 7 through 9, and were without a major protocol violation (eTable 1 in Supplement 1). The primary end point—the total number of gadolinium-enhancing lesions during months 7 through 9—was analyzed using a random-effects generalized linear model with a negative binomial distribution and logarithmic link function. This longitudinal model allows analysis of repeated MRI lesion counts for 3 months, taking into account the within-participant correlation of measurements. Fixed variables were treatment group, month, geographical region, logarithm of the last eligible screening gadolinium-enhancing lesion count, and logarithm of the baseline gadolinium-enhancing lesion count. This model (best-fitting count data) was prespecified in the statistical analysis plan and estimates the treatment difference and corresponding 95% CI for brand drug and generic drug in the log scale. Back-transformation results in the ratio of generic drug to brand drug and corresponding 95% CI. To assess study sensitivity, placebo data were also included in the model, resulting in the ratios and 95% CIs for the combined generic drug and brand drug treatment group and the individual treatments over placebo. Participants with at least 1 MRI assessment in months 7 through 9 were included in the analysis. No imputation was performed for missing MRI data. The other end points (number and volume of T2-weighted hyperintense lesions, volume of T1-weighted hypointense lesions, combined unique active lesions, brain volume, EDSS change, annualized relapse rate, and disease activity free) were not formally tested but were summarized per treatment group with point estimates and 95% CIs using an appropriate covariance model that included the stratification variables as covariates. A software program (SAS, version 9.4; SAS Institute Inc) was used for statistical analyses.

Results
Baseline Characteristics and Follow-up

Of 1549 participants screened, 796 were randomized. Screening failures resulted predominantly from the requirement for 1 to 15 gadolinium-enhancing lesions. Among screened participants, 50.9% (753 of 1480) did not have 1 to 15 gadolinium-enhancing lesions on the first MRI. Of these individuals, 298 underwent a second screening MRI, of which 101 (33.9%) were eligible, and 113 underwent a third screening MRI, of which 25 (22.1%) were eligible. Baseline demographic and disease characteristics were balanced among the treatment groups (Table 1). Overall, 735 participants (92.3%) completed the 9-month follow-up receiving randomized study drug, with similar proportions in the 3 treatment groups (Figure 1).

MRI Outcomes

The estimated mean numbers of gadolinium-enhancing lesions during months 7 through 9 for the combined generic drug and brand drug groups and each separately were significantly lower than for the placebo group (P < .001 for all) (Table 2 and Figure 2A), confirming study sensitivity. The mean numbers of gadolinium-enhancing lesions during months 7 through 9 estimated by the longitudinal model that included the 2 active treatment groups were 0.45 (generic drug) and 0.41 (brand drug), resulting in a ratio of generic drug to brand drug of 1.095 (95% CI, 0.883-1.360). This point estimate and 95% CI are fully contained within the predefined equivalence margin of 0.727 to 1.375 (Figure 2B). In the per-protocol set, the estimated ratio of generic drug to brand drug was 1.097 (95% CI, 0.880-1.368), supporting the primary analysis. Post hoc analysis of only new gadolinium-enhancing lesions during months 7 through 9 also supported the primary analysis (eTable 2 in Supplement 1). The 95% CIs for the other lesion-related MRI end points for the generic drug and brand drug treatment groups substantially overlapped. The mean changes in brain volume over 9 months were modest and similar across the 3 treatment groups.

Clinical Outcomes

The estimated annualized relapse rates were 0.31 (95% CI, 0.20-0.48) for generic drug, 0.40 (95% CI, 0.26-0.62) for brand drug, and 0.38 (95% CI, 0.22-0.66) for placebo (Table 2). The percentages of participants confirmed relapse free were 79.3% (280 of 353), 73.9% (264 of 357), and 73.8% (62 of 84) in the generic drug, brand drug, and placebo groups, respectively. The mean EDSS score was stable in the 3 treatment groups. The percentages of participants disease activity free were 9.3% (33 of 353) in the generic drug group, 9.2% (33 of 357) in the brand drug group, and 7.1% (6 of 84) in the placebo group.

Tolerability and Safety

Similar proportions of participants (range, 51.0%-56.0%) in the 3 treatment groups reported adverse events (Table 3 and eTable 3 in Supplement 1). Adverse events that were of severe intensity, were serious, or led to discontinuation of study medication or participation in the trial were infrequent and reported by similar proportions of generic drug–treated and brand drug–treated participants. The most common serious adverse events were MS relapse (2 generic drug participants and 4 brand drug participants), bronchitis (2 brand drug participants), anaphylactoid reaction (1 generic drug participant and 1 brand drug participant), and angioedema (1 generic drug participant and 1 brand drug participant). All other serious adverse events occurred in single participants.

Adverse events related to local injection site reactions occurred in similar proportions of participants treated with generic drug (22.9% [81 of 353]) and brand drug (23.2% [83 of 357]) compared with 16.7% (14 of 84) of placebo participants (eTable 4 in Supplement 1). Immediate postinjection reactions occurred in 6.8% (24 of 353) of generic drug participants, in 5.0% (18 of 357) of brand drug participants, and in no placebo participants (eTable 5 in Supplement 1). Based on participant self-assessment at day 1, injection site reactions with generic drug and brand drug were most apparent 5 minutes after injection, with median local injection site reaction scores of 2, which decreased to median scores of 0 at 24 hours. Proportions of participants scoring 0 to 5 injection site symptoms were similar in the generic drug and brand drug groups at 5 minutes and 24 hours after injection during the initial and month 3 reporting periods (eFigure in Supplement 1). Clinically significant vital sign or laboratory abnormalities were uncommon in all 3 treatment groups.

Discussion

The GATE study, to our knowledge, is the first phase 3 clinical trial to date of a generic disease-modifying medication for MS. Extensive physicochemical characterization of generic drug showed comparable results to brand drug in a wide range of orthogonal chemical, biochemical, biological, and nonclinical toxicology studies (Roel Fokkens, PhD, and Roel Arends, PhD, unpublished data, 2011). A randomized, double-blind, crossover phase 1 trial in 20 healthy volunteers demonstrated generic glatiramer acetate to have good safety and injection site tolerability, similar to those of brand glatiramer acetate.27 The well-powered, randomized, double-blind, active and placebo-controlled trial reported herein showed that generic drug is effective and reduces gadolinium-enhancing lesions in RRMS to the same extent as brand drug. Formal equivalence margins for other MRI and clinical end points were not defined, but the 95% CIs for the generic drug and brand drug groups for these end points substantially overlapped. Generic drug had a benign safety and tolerability profile for 9 months, similar to that of brand drug. The GATE study supported equivalence of generic glatiramer acetate to the originator brand glatiramer acetate.

The US Food and Drug Administration recently approved another generic glatiramer acetate drug based on demonstration of physicochemical equivalence and equivalent biological and immunological effects in murine experimental autoimmune encephalomyelitis, without clinical testing.28,29 In contrast, the European Medicines Agency30 considered brand glatiramer acetate a complex nonbiological agent and required a clinical trial assessing efficacy, safety, and tolerability for generic glatiramer acetate. Based on regulatory input, we adopted an equivalence design, rather than noninferiority, and inclusion of a placebo group to show study sensitivity. The study reported herein exemplifies the differences between how the 2 agencies approached generic glatiramer acetate.

In contrast to studies serving as the basis for regulatory approval of novel agents, which aim to show superiority compared with placebo or active comparator, studies of generic versions of approved agents aim to demonstrate equivalence. Therefore, the goals of this trial were distinct from those of previous trials in the field. The primary efficacy end point was gadolinium-enhancing lesion activity, which was expected to be more sensitive than the clinical outcomes of relapse rate or disability accrual typically required in pivotal trials of novel agents. Because the correlation between MRI lesion activity and clinical manifestations is weak for individual patients, regulatory agencies generally consider imaging outcomes only to provide supportive evidence of efficacy. However, 2 meta-analyses of studies covering a broad range of MS therapies demonstrated that in RRMS not only are the mean treatment effects on MRI lesion activity and relapse rate strongly correlated at the clinical trial level31 but also the magnitude of the benefit on MRI lesion activity predicts the magnitude of the treatment effect on relapse rates.32 This observation supports the use of MRI markers as the primary end point in pivotal clinical trials in certain circumstances, such as evaluating a generic version of a drug with well-documented effects on MRI lesion activity and clinical relapse rates.30

The GATE study was not designed or anticipated to quantitatively reproduce results of the European/Canadian Glatiramer Acetate trial.4 Instead, it aimed to establish equivalence of generic glatiramer acetate and brand glatiramer acetate, taking advantage of information provided by the earlier study, which demonstrated that brand glatiramer acetate reduced gadolinium-enhanced lesions on monthly MRI for 9 months compared with placebo. The treatment effect on MRI lesion activity increased over time, becoming significant at month 6. Therefore, the GATE study used MRI during months 7 through 9. Eligibility criteria for both trials required at least 1 gadolinium-enhancing lesion on screening MRI. In the GATE study, participants with at least 15 gadolinium-enhancing lesions on screening MRI were excluded to avoid enrolling participants with highly active disease in a placebo-controlled trial.

This trial had several potential limitations. First, adverse events related to injection site reactions occurred less often with placebo compared with the active treatments, which potentially could have led to partial unmasking. However, the 3 study treatments had identical appearances and contained the same excipients, and some local injection site reactions occurred in placebo-treated participants, albeit at a lower frequency. Most important, the generic glatiramer acetate and brand glatiramer acetate groups had similar adverse event profiles. Second, the trial was not designed or formally powered to show relapse rate reduction in a population accessible for clinical trials today. With only 84 placebo participants, expected power to demonstrate benefit on relapses was less than 30%; therefore, benefit on relapses relative to placebo was not confirmed. Nevertheless, brand glatiramer acetate consistently reduced relapses in previous trials.211 Third, the duration of the trial was short. All participants completing the double-blind portion of the trial were eligible to receive generic glatiramer acetate treatment in a 15-month open-label extension. To help assess interchangeability of generic drug and brand drug, this extension will provide additional data on long-term efficacy and safety, immunogenicity, and the effect of switching from brand glatiramer acetate to generic glatiramer acetate treatment.

Conclusions

The GATE study, to our knowledge, is the first phase 3 clinical trial to date of a generic disease-modifying medication for MS. The patents for the first approved treatments for RRMS are expiring, creating the opportunity to develop generic alternatives, with the goal of cost savings for payers and patients. The development of generic glatiramer acetate illustrates the challenges in developing generic biological and complex nonbiological agents. The GATE study demonstrated equivalent efficacy, safety, and tolerability for generic glatiramer acetate and brand glatiramer acetate as treatment for RRMS. These results may allow for a generic alternative to the originator brand glatiramer acetate, an RRMS treatment with established long-term efficacy and safety.

Back to top
Article Information
Section Editor: Ira Shoulson, MD.

Accepted for Publication: July 3, 2015.

Corresponding Author: Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Mellen Center Desk U-10, 9500 Euclid Ave, Cleveland, OH 44195 (cohenj@ccf.org).

Published Online: October 12, 2015. doi:10.1001/jamaneurol.2015.2154.

Author Contributions: Dr Cohen had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Cohen, Wolf, Oberyé, van den Tweel.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Mulder.

Conflict of Interest Disclosures: Dr Cohen reported being a coeditor of Multiple Sclerosis Journal–Experimental, Translational and Clinical and reported receiving personal fees from EMD Serono, Genentech, Genzyme, Innate Immunotherapeutics, and Vaccinex, all outside of the present work. Dr Selmaj reported receiving grants and personal fees from Synthon BV during the conduct of the study, and outside of the present work reported receiving grants and personal fees from Roche, Biogen Idec, Novartis, Teva, Merck, Genzyme, and Receptos and receiving grants from Neuron. Dr Wolf reported receiving personal fees from Synthon BV during the conduct of the study and reported receiving personal fees from Novartis, Teva, BBB Therapeutics BV, and Desitin GmbH outside of the present work. Dr Sormani reported receiving personal fees from Synthon BV during the conduct of the study and reported receiving personal fees from Biogen Idec, Teva, Merck, Novartis, Genzyme, and Roche outside of the present work. Ms Oberyé, Drs van den Tweel and Koper, and Messrs Mulder and Voortman reported receiving personal fees from Synthon BV during the conduct of the study and outside of the present work. Dr Barkhof reported receiving personal fees from Bayer Schering Pharma, Sanofi Aventis, Biogen Idec, Teva, Merck, Novartis, Roche, Synthon BV, Jansen Research, and Genzyme, all outside of the present work. No other disclosures were reported.

Funding/Support: The Glatiramer Acetate Clinical Trial to Assess Equivalence With Copaxone (GATE) study was funded by Synthon BV.

Role of the Funder/Sponsor: In collaboration with the other authors, the study sponsor (Synthon BV) was responsible for the design and undertaking of the trial, the data analysis and interpretation, the writing of the manuscript, and the decision to submit the manuscript for publication.

Group Information: Members of the phase 3 Glatiramer Acetate Clinical Trial to Assess Equivalence With Copaxone (GATE) study group are listed in the eMethods in Supplement 1.

Additional Contributions: Gavin Giovannoni, MD (Centre for Neuroscience and Trauma, Barts and The London Medical School, London, England), Ernst Wilhelm Radü, MD (Medical Image Analysis Center, Basel, Switzerland), and Andreas Völp, PhD (Psy Consult Scientific Services, Frankfurt, Germany) were members of the data and safety monitoring board. All data and safety monitoring board members were compensated for the work performed in relation to this trial (ie, for data analysis and review). No other compensation was provided to them. We thank the trial site personnel (listed in the eMethods in Supplement 1) and the patients who participated in the study.

References
1.
Racke  MK, Lovett-Racke  AE, Karandikar  NJ.  The mechanism of action of glatiramer acetate treatment in multiple sclerosis. Neurology. 2010;74(suppl 1):S25-S30.
PubMedArticle
2.
Bornstein  MB, Miller  A, Slagle  S,  et al.  A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N Engl J Med. 1987;317(7):408-414.
PubMedArticle
3.
Johnson  KP, Brooks  BR, Cohen  JA,  et al; Copolymer 1 Multiple Sclerosis Study Group.  Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. Neurology. 1995;45(7):1268-1276.
PubMedArticle
4.
Comi  G, Filippi  M, Wolinsky  JS; European/Canadian Glatiramer Acetate Study Group.  European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging–measured disease activity and burden in patients with relapsing multiple sclerosis. Ann Neurol. 2001;49(3):290-297.
PubMedArticle
5.
Comi  G, Martinelli  V, Rodegher  M,  et al; PreCISe Study Group.  Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial [published correction appears in Lancet. 2010;375(9724):1436]. Lancet. 2009;374(9700):1503-1511.
PubMedArticle
6.
Mikol  DD, Barkhof  F, Chang  P,  et al; REGARD Study Group.  Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the Rebif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol. 2008;7(10):903-914.
PubMedArticle
7.
Cadavid  D, Wolansky  LJ, Skurnick  J,  et al.  Efficacy of treatment of MS with IFNβ-1b or glatiramer acetate by monthly brain MRI in the BECOME study. Neurology. 2009;72(23):1976-1983.
PubMedArticle
8.
O’Connor  P, Filippi  M, Arnason  B,  et al; BEYOND Study Group.  250 µg or 500 µg Interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study [published corrections appear in Lancet Neurol. 2011;10(2):115, 2009;8(11):981, and 2012;11(1):27].  Lancet Neurol. 2009;8(10):889-897.
PubMedArticle
9.
Comi  G, Cohen  JA, Arnold  DL, Wynn  D, Filippi  M; FORTE Study Group.  Phase III dose-comparison study of glatiramer acetate for multiple sclerosis. Ann Neurol. 2011;69(1):75-82.
PubMedArticle
10.
Fox  RJ, Miller  DH, Phillips  JT,  et al; CONFIRM Study Investigators.  Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis [published correction appears in N Engl J Med. 2012;367(17):1673]. N Engl J Med. 2012;367(12):1087-1097.
PubMedArticle
11.
Lublin  FD, Cofield  SS, Cutter  GR,  et al; CombiRx Investigators.  Randomized study combining interferon and glatiramer acetate in multiple sclerosis. Ann Neurol. 2013;73(3):327-340.
PubMedArticle
12.
Ford  C, Goodman  AD, Johnson  K,  et al.  Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: results from the 15-year analysis of the US prospective open-label study of glatiramer acetate. Mult Scler. 2010;16(3):342-350.
PubMedArticle
13.
Hartung  DM, Bourdette  DN, Ahmed  SM, Whitham  RH.  The cost of multiple sclerosis drugs in the US and the pharmaceutical industry: too big to fail? Neurology. 2015;84(21):2185-2192.
PubMedArticle
14.
Hauser  SL, Johnston  SC.  Multiple sclerosis drugs: sticker shock. Ann Neurol. 2012;71(5):A5-A6.
PubMedArticle
15.
Woodcock  J, Griffin  J, Behrman  R,  et al.  The FDA’s assessment of follow-on protein products: a historical perspective. Nat Rev Drug Discov. 2007;6(6):437-442.
PubMedArticle
16.
Reingold  SC, Steiner  JP, Polman  CH,  et al.  The challenge of follow-on biologics for treatment of multiple sclerosis. Neurology. 2009;73(7):552-559.
PubMedArticle
17.
Schellekens  H, Klinger  E, Mühlebach  S, Brin  JF, Storm  G, Crommelin  DJ.  The therapeutic equivalence of complex drugs. Regul Toxicol Pharmacol. 2011;59(1):176-183.
PubMedArticle
18.
Mühlebach  S, Vulto  A, de Vlieger  JS, Weinstein  V, Flühmann  B, Shah  VP.  The authorization of non-biological complex drugs (NBCDs) follow-on versions: specific regulatory and interchangeability rules ahead? GaBi J. 2013;2(4):204-207. doi:10.5639/gabij.2013.0204.054.Article
19.
Schellekens  H, Stegemann  S, Weinstein  V,  et al.  How to regulate nonbiological complex drugs (NBCD) and their follow-on versions: points to consider. AAPS J. 2014;16(1):15-21.
PubMedArticle
20.
Ventola  CL.  Biosimilars, part 1: proposed regulatory criteria for FDA approval. P T. 2013;38(5):270-287.
PubMed
21.
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonised tripartite guideline: guideline for good clinical practice: E6(R1). Current step 4 version dated June 10, 1996. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf. Accessed September 28, 2014.
22.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053.
PubMedArticle
23.
Polman  CH, Reingold  SC, Banwell  B,  et al.  Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302.
PubMedArticle
24.
Kurtzke  JF.  Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology. 1983;33(11):1444-1452.
PubMedArticle
25.
Anderson  G, Meyer  D, Herrman  CE,  et al.  Tolerability and safety of novel half milliliter formulation of glatiramer acetate for subcutaneous injection: an open-label, multicenter, randomized comparative study. J Neurol. 2010;257(11):1917-1923.
PubMedArticle
26.
Havrdova  E, Galetta  S, Hutchinson  M,  et al.  Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study. Lancet Neurol. 2009;8(3):254-260.
PubMedArticle
27.
Oberye  J, van den Tweel  E, Mulder  M, Voortman  G, Hooftman  L.  Randomised, double-blind, cross-over trial of GTR (generic glatiramer acetate) in healthy volunteers shows similar tolerability and safety to Copaxone (P477) [abstract]. J Neurol. 2012;259(suppl 1):S113. doi:10.1007/s00415-012-6524-4.
28.
US Food and Drug Administration. FDA approves first generic Copaxone to treat multiple sclerosis. For immiediate release April 15, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm443143.htm. Accessed September 7, 2015.
29.
Citizen petition denial letter from CDER to Teva Pharmaceuticals. Date posted April 16, 2015. http://www.regulations.gov/#!documentDetail;D=FDA-2015-P-1050-0012. Accessed September 7, 2015.
30.
European Medicines Agency. Guideline on similar biological medicinal products containing interferon beta. Adopted December 15, 2011. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/01/WC500120652.pdf. Accessed September 1, 2015.
31.
Sormani  MP, Bonzano  L, Roccatagliata  L, Cutter  GR, Mancardi  GL, Bruzzi  P.  Magnetic resonance imaging as a potential surrogate for relapses in multiple sclerosis: a meta-analytic approach. Ann Neurol. 2009;65(3):268-275.
PubMedArticle
32.
Sormani  MP, Bruzzi  P.  MRI lesions as a surrogate for relapses in multiple sclerosis: a meta-analysis of randomised trials. Lancet Neurol. 2013;12(7):669-676.
PubMedArticle
×