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Bioequivalence of Biosimilar Tumor Necrosis Factor-α Inhibitors Compared With Their Reference Biologics: A Systematic ReviewBiosimilar TNF-α Inhibitors Compared With Reference Biologics ONLINE FIRST

Francine Chingcuanco, MHS; Jodi B. Segal, MD, MPH; Seoyoung C. Kim, MD, ScD, MSCE; and G. Caleb Alexander, MD
[+] Article, Author, and Disclosure Information

This article was published at www.annals.org on 2 August 2016.


From Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, and Brigham and Women's Hospital, Boston, Massachusetts.

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 to 3 and Appendix Tables 1to 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, galexand@jhsph.edu.

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.


Ann Intern Med. Published online 2 August 2016 doi:10.7326/M16-0428
© 2016 American College of Physicians
Text Size: A A A

Background: Biosimilars are of growing clinical, regulatory, and commercial importance.

Purpose: To summarize evidence about the bioequivalence between biosimilar and reference tumor necrosis factor-α (TNF-α) inhibitors.

Data Sources: 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.

Study Selection: 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.

Data Extraction: Two reviewers independently screened titles and abstracts, extracted data from selected studies, and assessed study quality.

Data Synthesis: 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.

Limitation: Possible publication bias, small sample sizes of many studies, and lack of published studies for several biosimilars.

Conclusion: Preliminary evidence supports the biosimilarity and interchangeability of biosimilar and reference TNF-α inhibitors.

Primary Funding Source: Johns Hopkins Center of Excellence in Regulatory Science and Innovation. (PROSPERO: CRD42015025262)

Figures

Grahic Jump Location
Appendix Figure 1.

Evidence search and selection.

TNF-α = tumor necrosis factor-α.

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Appendix Figure 2.

Risk of bias in randomized, controlled trials.

Attrition bias based on primary end point identified by authors. Specific end points identified in Table 3. Other biases include the risk of bias due to conflict of interest (for example, authors employed by, held stock in, or received funds from manufacturer). Green boxes with a plus sign indicate low risk of bias. Yellow boxes with a question mark indicate unclear risk of bias. Red boxes with a minus sign indicate high risk of bias.

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Appendix Figure 3.

Risk of bias in observational studies.

Other biases include the risk of bias due to conflict of interest (for example, authors employed by, held stock in, or received funds from the manufacturer); lack of temporality for cross-sectional studies; heterogeneity when patients were switched between originator and biosimilar products; and small sample size. Green boxes with a plus sign indicate low risk of bias. Yellow boxes with a question mark indicate unclear risk of bias. Red boxes with a minus sign indicate high risk of bias.

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Tables

References

Letters

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Comments

Submit a Comment/Letter
Conclusions about Interchangeability of anti-TNF Biosimilars are Premature
Posted on August 2, 2016
David T. Rubin, MD, FACP
University of Chicago Medicine, Crohn's and Colitis Foundation of America
Conflict of Interest: I have served as a consultant and received grants support for institutional clinical trials from AbbVie, Janssen, UCB, Takeda, Pfizer, Amgen and Prometheus Laboratories. I am a consultant for Samsung/Bioepis.

To the Editors,

For the most part, I agree with the findings by Chingcuanco, et al. and do not fault the methodology related to the "bioequivalence" of the anti-TNF biosimilars with their reference/originator drugs.

I do have an issue, however, with a conclusion about interchangeability, which is not just about the ability to switch in one direction, but includes the ability to switch back and forth between agents. To date there has not been any study that looked at this question thoroughly. In addition, even when considering studies of switching in one direction, there remains insufficient evidence to support the conclusion that this is safe. The small cohort studies in which switching has been reported are limited in direction and in the number of switches.

As the authors mention, the development of anti-drug antibodies may result in loss of response to the drug and potentially, life threatening drug reactions. Conclusions that biosimilars to anti-TNFs are "interchangeable" with each other or with the originator drugs are premature and not supported by the limited, underpowered and heterogenous available evidence.

I'm surprised that this article can include the conclusion about interchangeability with such limited information, and would have encouraged the editors to exclude such a strong endorsement based on such limited information. This manuscript may be inappropriately used by payers to justify "non-medical" switches in favor of cost savings. A savings, by the way, that is NOT expected to be translated to patients in the form of reduced premiums, less co-payment or increased access.

In the Crohn's and Colitis Foundation of America's position statement about biosimilars, we have been careful to distinguish the issue of extrapolation from that of interchangeability, and I refer you to that statement:

http://www.ccfa.org/assets/pdfs/advocacy/biosimilar-position-statement.pdf

Thank you.

David T. Rubin, MD, FACP
Professor of Medicine
University of Chicago Medicine
Chair, Crohn's and Colitis Foundation of America Government and Industry Affairs Committee
Submit a Comment/Letter

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