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Equivalence and switching between biosimilars and reference molecules in rheumatoid arthritis: protocol for two systematic reviews and meta-analyses
Bruna de Oliveira Ascef
Universidade de Sao Paulo
Corresponding Author
ORCiD: https://orcid.org/0000-0002-2744-3974
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background Biologic drugs such as adalimumab, etanercept, and infliximab represent major first-line and second-line treatments for rheumatoid arthritis (RA) patients. However, their high cost poses a massive burden on healthcare systems worldwide. The expiration of patents for these biologics has driven to the production of biosimilar drugs, which are potentially less costly and remarkably similar, albeit not identical to the reference molecules. These two systematic reviews aim to investigate the efficacy and safety profile of biosimilars compared to biologics (systematic review 1) and the impact of switching between biosimilar drugs and reference biologics on the management of RA patients (systematic review 2).
Methods Electronic searches will be performed through MEDLINE (via Pubmed), EMBASE, LILACS, and CENTRAL (from inception to September 2020). Risk of bias assessments will be carried out with the Cochrane risk of bias tool, supplemented with specific domains from equivalence trials. Random-effects models will be fitted to obtain summary estimates using either relative risk or standardized mean difference as a metric. Between-trial heterogeneity will be tested and quantified with the Q-test and I2 metric, respectively, whereas assessment of small-study bias will be examined through contour-enhanced funnel plots and Egger and Harbord's tests. Meta-regression models will be fitted when appropriate. The primary outcome will be the rate of treatment success according to the American College of Rheumatology 20 (ACR20) and the co-primary outcome will be the Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index). Conclusions will be based on equivalence hypothesis testing using predefined margins of equivalence elicited from a group of experienced rheumatologists and prior studies. The overall certainty of evidence will be assessed based on the GRADE system.
Discussion The two systematic reviews described here, to the best of our knowledge, are the first ones proposing a comprehensive, clinician-oriented approach to assess the equivalence and the impact of switching between biosimilars and biologics on the management of patients with RA. The results will elucidate the efficacy, safety, immunogenicity of biosimilars, and the clinical consequences of substituting biologics with biosimilars in the management of RA.
Systematic Review Registration Protocol synopses were previously registered on PROSPERO (CRD42019137152 and CRD42019137155).
Keywords
Biosimilar Pharmaceuticals, Etanercept, Infliximab, Adalimumab, Arthritis, Rheumatoid
Figure 1
This is a list of supplementary files associated with this preprint. Click to download.
- Additionalfile1.docx
Additional file 1. PRISMA for systematic review protocols (PRISMA-P) Checklist. Source: Moher et al. (21)
- Additionalfile2.docx
Additional file 2. Search Strategies of electronic database and other sources.
- Additionalfile3.docx
Additional file 3. Secondary outcomes of efficacy (disease activity measures, functional capacity, quality of life and structural damage progression) and safety. ACR: the American College of Rheumatology; CRP: C-Reactive Protein level; VAS: visual analog scale; HAQ-DI: Health Assessment Questionnaire - Disability Index; VAS: visual analog scale; SDAI: Simplified Disease Activity Score DA: disease activity; CDAI: Clinical Disease Activity Score DAS28-ESR: Disease Activity Score in 28 joints based on the erythrocyte sedimentation rate; DAS28-CRP: Disease Activity Score in 28 joints, four components based on C-reactive protein; SJC: Swollen joint count; TJC: Tender Joint Count; ACR-N: The numeric index of the ACR response; EULAR: European League Against Rheumatism; SF-36: The Medical Outcomes Study 36-item Short-Form Health Survey; mTRSS: Sharp/van der Heijde score; TEAE: Overall Treatment Emergent Adverse Event; infusion-related reactions.
- Additionalfile4.docx
Additional file 4. Criteria to identify bias on equivalence or non-inferiority studies. Sources: Cochrane Risk of Bias in randomized trials (ROB 1.0.) (35) and the US Agency for Healthcare Research and Quality recommendations (23).
- Additionalfile5.docx
Additional file 5. Criteria to identify bias on switching studies. Notes: * It must be clearly pointed out. The wash-out period is defined as the time between the discontinuation of one biologic and the initiation of a second biologic. This wash-out period is arbitrarily based on the half-life of the biologic, namely the time needed to eliminate 50% of the biologic from the bloodstream.; ** The comparative assessment should occur during the final exposure period after enough time (i.e., an adequate washout period of at least three or more half-lives) has elapsed following the last administration of the reference product in the switching arm; The number of doses of the proposed interchangeable product or reference product administered in the final exposure period will depend on the half-life and clinical dosing regimen.; The serum half-time of infliximab is around 14 days or 2 weeks; Etanercept has a mean ± standard deviation half-life of 102 ± 30 hours was observed ( more or less 4 days); The mean terminal half-life of adalimumab was approximately 2 weeks. Sources: Moots et al.(27) and FDA (14).
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This preprint is under consideration at Systematic Reviews. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Protocol
Equivalence and switching between biosimilars and reference molecules in rheumatoid arthritis: protocol for two systematic reviews and meta-analyses
Bruna de Oliveira Ascef
Universidade de Sao Paulo
Corresponding Author
ORCiD: https://orcid.org/0000-0002-2744-3974
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 21 Sep, 2020
No community comments so far
First submitted
On 17 Sep, 2020
Submission checks complete
On 17 Sep, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Drug Discovery, Design, & Development
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background Biologic drugs such as adalimumab, etanercept, and infliximab represent major first-line and second-line treatments for rheumatoid arthritis (RA) patients. However, their high cost poses a massive burden on healthcare systems worldwide. The expiration of patents for these biologics has driven to the production of biosimilar drugs, which are potentially less costly and remarkably similar, albeit not identical to the reference molecules. These two systematic reviews aim to investigate the efficacy and safety profile of biosimilars compared to biologics (systematic review 1) and the impact of switching between biosimilar drugs and reference biologics on the management of RA patients (systematic review 2).
Methods Electronic searches will be performed through MEDLINE (via Pubmed), EMBASE, LILACS, and CENTRAL (from inception to September 2020). Risk of bias assessments will be carried out with the Cochrane risk of bias tool, supplemented with specific domains from equivalence trials. Random-effects models will be fitted to obtain summary estimates using either relative risk or standardized mean difference as a metric. Between-trial heterogeneity will be tested and quantified with the Q-test and I2 metric, respectively, whereas assessment of small-study bias will be examined through contour-enhanced funnel plots and Egger and Harbord's tests. Meta-regression models will be fitted when appropriate. The primary outcome will be the rate of treatment success according to the American College of Rheumatology 20 (ACR20) and the co-primary outcome will be the Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index). Conclusions will be based on equivalence hypothesis testing using predefined margins of equivalence elicited from a group of experienced rheumatologists and prior studies. The overall certainty of evidence will be assessed based on the GRADE system.
Discussion The two systematic reviews described here, to the best of our knowledge, are the first ones proposing a comprehensive, clinician-oriented approach to assess the equivalence and the impact of switching between biosimilars and biologics on the management of patients with RA. The results will elucidate the efficacy, safety, immunogenicity of biosimilars, and the clinical consequences of substituting biologics with biosimilars in the management of RA.
Systematic Review Registration Protocol synopses were previously registered on PROSPERO (CRD42019137152 and CRD42019137155).
Figure 1