Francine Chingcuanco, MHS; Jodi B. Segal, MD, MPH; Seoyoung C. Kim, MD, ScD, MSCE; G. Caleb Alexander, MD
Acknowledgment: The authors thank Dora Lin, Lori Rosman, and Eleanor Lucas for their assistance in study search, screening, and data abstraction and Gillian Gresham and Sheriza Baksh for their assistance with the quality assessment of included studies.
Grant Support: In part by the Johns Hopkins Center of Excellence in Regulatory Science and Innovation (grant U01 FD004977-01).
Disclosures: Dr. Kim reports grants from Pfizer, AstraZeneca, Bristol-Myers Squibb, Lilly, and Genentech outside the submitted work. Dr. Alexander reports contracts from the FDA during the conduct of the study; he is also chair of the FDA's Peripheral and Central Nervous System Advisory Committee; a paid consultant to PainNavigator, a mobile startup to improve patients' pain management; a paid consultant to IMS Health; and serves on an IMS Health scientific advisory board. This arrangement has been reviewed and approved by Johns Hopkins University in accordance with its conflict of interest policies. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-0428.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement: Study protocol: See www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015025262. Statistical code: Not applicable. Data set: See Tables 1, 2, 3 and Appendix Tables 1, 2, 3, 4, 5, 6 and 7.
Requests for Single Reprints: G. Caleb Alexander, MD, MS, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street W6035, Baltimore, MD 21205; e-mail, firstname.lastname@example.org.
Current Author Addresses: Ms. Chingcuanco and Dr. Alexander: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street W6035, Baltimore, MD 21205.
Dr. Segal: Johns Hopkins Bloomberg School of Public Health, Hampton House, 624 North Broadway, Room 644, Baltimore, MD 21205.
Dr. Kim: Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, 1620 Tremont Street, Suite 3030, Boston, MA 02115.
Author Contributions: Conception and design: F. Chingcuanco, J.B. Segal, S.C. Kim, G.C. Alexander.
Analysis and interpretation of the data: F. Chingcuanco, J.B. Segal, G.C. Alexander.
Drafting of the article: F. Chingcuanco, S.C. Kim, G.C. Alexander.
Critical revision of the article for important intellectual content: F. Chingcuanco, J.B. Segal, S.C. Kim, G.C. Alexander.
Final approval of the article: F. Chingcuanco, J.B. Segal, S.C. Kim, G.C. Alexander.
Provision of study materials or patients: G.C. Alexander.
Statistical expertise: F. Chingcuanco.
Obtaining of funding: G.C. Alexander.
Administrative, technical, or logistic support: G.C. Alexander.
Collection and assembly of data: F. Chingcuanco, G.C. Alexander.
Biosimilars are of growing clinical, regulatory, and commercial importance.
To summarize evidence about the bioequivalence between biosimilar and reference tumor necrosis factor-α (TNF-α) inhibitors.
PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and LILACS from inception through 13 April 2016 and ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, EU Clinical Trials Register, U.S. Food and Drug Administration, and European Medicines Agency from inception through 30 April 2016.
Published English-language studies of any size or design that compared the pharmacokinetics, clinical efficacy, adverse events, or immunogenicity of a biosimilar TNF-α inhibitor with a reference biologic in humans.
Two reviewers independently screened titles and abstracts, extracted data from selected studies, and assessed study quality.
Of 19 eligible studies, 8 were phase 1 randomized trials, 5 were phase 3 randomized trials, and 6 were observational studies. Most phase 1 trials (n = 7) involved healthy volunteers, phase 3 trials involved patients with rheumatoid arthritis, and observational studies involved those with rheumatoid arthritis or inflammatory bowel disease. All phase 1 trials showed that pharmacokinetic parameters of the biosimilar and respective biologic were within the prespecified equivalence margin of 80% to 125%. Phase 3 trials suggested similar clinical responses and adverse events. Adverse events were usually of mild to moderate severity. Two cross-sectional observational studies showed cross-reactivity between products, whereas 4 cohort studies of patients switched from reference to biosimilar products suggested similar efficacy and safety outcomes.
Possible publication bias, small sample sizes of many studies, and lack of published studies for several biosimilars.
Preliminary evidence supports the biosimilarity and interchangeability of biosimilar and reference TNF-α inhibitors.
Johns Hopkins Center of Excellence in Regulatory Science and Innovation. (PROSPERO: CRD42015025262)
Chingcuanco F, Segal JB, Kim SC, Alexander GC. Bioequivalence of Biosimilar Tumor Necrosis Factor-α Inhibitors Compared With Their Reference Biologics: A Systematic Review. Ann Intern Med. 2016;165:565–574. doi: 10.7326/M16-0428
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Published: Ann Intern Med. 2016;165(8):565-574.
Published at www.annals.org on 2 August 2016
Gastroenterology/Hepatology, Inflammatory Bowel Disease.
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