Effectiveness, Uses and Safety of Granulocyte Colony Stimulating Factor biosimilars: a protocol for systematic review and meta-analysis
Authors: Ukoma Chi-kadibia Theophilus , Nna Emmanuel Okechukwu , Okoye Helen Chioma , Duru Augustine Nwakuche , Ngene Samuel Osobuchi , Nnamani Amaka Obiageli , Ikeagwulonu Richard Chinaza , Ezeonu Chinonyelum Thecla , Daboer Jonathan C , Asiegbu Uzoma Vivian , Odimegwu Chioma Laura , Okoye Ifeoma Joy 
Published: February 2021

Abstract
Background Granulocyte Colony-stimulating factors (G-CSF) biosimilars are recombinant biologics that are similar to a reference product, neupogen, a 175 amino acid recombinant human G-CSF. Characteristically, biosimilars are produced from living cells as high molecular weight, heterogenous compounds that are highly immunogenic. They are primarily used to treat febrile and severe neutropenia in oncology patients as well as mobilize peripheral stem cells in transplant donors. However, as biosimilars are produced by biological processes rather than chemical synthesis, their comparable effectiveness and safety are very paramount to clinical uses. We aimed to produce a protocol for consistent and accurate systematic review and meta-analysis of G-CSF biosimilars.Methods We developed a search strategy using MeSH terms, key words and entry terms to search 9 databases: PubMed, AJOL, Embase, Google Scholar, Scopus, Cochrane Library, CINAHL, Web of Science and ResearchGate. Only randomized controlled trials retreivable in the English language will be included in this study. The primary measurable outcomes in this study are uses, effectiveness and safety of G-CSF biosimilars. Identified primary studies will be screened, deduplicated and selected based on study design, inclusion/exclusion criteria and outcome measures using DistillerSR software. Studies will be assessed for methodological, clinical and statistical heterogeneity. Extractable data items for effectiveness measure are: i) proportion of patients with 50% increase in absolute neutrophil count within 3–7 days; ii) resolution of fever within 3–7 days, iii) resolution of intra-oral mucosa ulcers within 7–10 days and iv) resoluton of difficulty in swallowing within 7–10 days. Measures of safety are i) proportion of patients with immunologic reactions, ii) any other documented adverse events. Quality scores and risk of bias for individual studies will be reported. Funnel Plots will be used for assessing publication bias in selected studies. Effect size, variance, SE and % CI and heterogeneity tests will be reported on forest plots using the CMA software version 3. Subgroup analysis and meta-regression will also be included using secondary outcomes as moderators and explanatory variables. The systematic review and meta-analysis will be reported according to PRISMA 2015 Statement.Discussion Ethical approval will not be required since this study will be based on published data. G-CSF biosimilars will be compared with the reference product, neupogen (filgrastin). The uses, effectiveness and safety of the biosimilars will be discussed. The study will also examine short and long acting biosimilars and compare their overall effectiveness. The strength of evidence from this study will be assessed using the NIH Quality assessment for systematic review and meta-analysis.Trial Registration Number The study is registered with PROSPERO, with registration number CRD42021232375