PONE-D-23-17848Safety outcomes when switching between biosimilars and reference biologics

 A systematic review and meta-analysisPLOS ONE

Dear Dr. Herndon,

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Additional Editor Comments:

Dear Authors,

Thank you for your submission and we are sorry it has been longer than expected to provide feedback on you manuscript. Following some comments from the reviewers for your consideration before a final decision:

The authors have analysed the impact of original-to-biosimilar switch or vice versa in randomized controlled studies (or extension studies), both from US FDA data bases, and published information. A statistical analytical approach has been applied to assess the impact of single or multiple switches on safety, including immunogenicity. No differences in the immunogenicity and safety profile have been identified in 5,252 patients included in the analysis.

General Comments-suggestions

The authors have put together a rigorous scientific manuscript that is worth being published. Reassuring healthcare professional based on evidence is of outmost relevance in order to foster biosimilar penetration and benefits.

While a few papers (meta-analysis) have been published on RWE safety outcomes as a result of switching from the original reference medicine to a biosimilar, this manuscript is of particular relevance given the authors affiliation, US FDA, the origin of the data analysed - US sourced data of controlled trials- and the statistical approach undertaken.

Specific Comments-suggestions (P = Page / L = Line)

A few comments are made below. Food for thought rather than actual major issues.

P2 L25

“Biosimilars are increasingly available for the treatment of many serious disorders, however concerns persist about switching a patient to a biosimilar whose condition is stable while on the reference biologic” I would suggest to slightly rephrase this sentence, or at the very least, put it into context.

Although certainly concerns have been raised, they are (1) overall progressively decreasing, (2) among healthcare market stakeholders mostly limited to prescribers (some prescribers and, as a results, patients), (3) probably more prevalent in the US than in Europe, or than in other reference jurisdictions with a more extended experience with biosimilars and (4) focused on complex biologics with specific safety profiles. It may sound a bit alarming and cause a to raise such upfront. In particular given the fact that the conclusion is that concern are unfounded based on evidence. (Same P3 / L39 and P20 / L365).

P3 L48

“Increasing the availability and use of biosimilars is an important public health strategy for reducing drug costs and increasing the availability of biological products to underserved populations” The authors may want to consider and state other benefits some using biosimilar may be worth

being mentioned in spite of the fact that the manuscript focuses on patient access (foster innovation, prevent shortages, etc).

Material and methods section

- It is assumed that all the switching studies included in the analysis were conducted in order to claim interchangeability designation. Correct? Did any of the studied biosimilar candidates analysed not obtain interchangeability designation?

- Forty four distinct STPs were identified from thirty-one unique studies. This is an important piece of information since there may be a patient, centre, protocol and/or investigator’s impact on the outcome. Is this accounted for in the statistical analysis? For instance a patient undergoing a switch and claiming an ADR may again claim an ADR in a different STP (possibly owing to nocebo effect).

Results and discussion

- No differences have been found, yet nocebo effect is found in clinical practice Nosuch an effect is observed in RCT?

P18 L311

“The findings in this report raise several timely questions regarding the data needed to support approval of biosimilars and how to address regulatory requirements unique to the BPCI Act for the “interchangeable” designation..” How about using this kind of studies in order to withdraw the interchangeability designation in the long run? Would that be appropriate/feasible?

P19 L337

“Limitations of this review include the small number of patients in the safety evaluations from some source material..” Isn’t the number of patients being taken not consideration in the statistical analysis?

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #1: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: Yes

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5. Review Comments to the Author

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Reviewer #1: Please, see file attached

Ms: PONE-D-23-17848

“Safety outcomes when switching between biosimilars and reference biologics. A systematic review and meta-analysis”

The authors have analysed the impact of original-to-biosimilar switch or vice versa in randomized controlled studies (or extension studies), both from US FDA data bases, and published information. A statistical analytical approach has been applied to assess the impact of single or multiple switches on safety, including immunogenicity. No differences in the immunogenicity and safety profile have been identified in 5,252 patients included in the analysis.

General Comments-suggestions

The authors have put together a rigorous scientific manuscript that is worth being published. Reassuring healthcare professional based on evidence is of outmost relevance in order to foster biosimilar penetration and benefits.

While a few papers (meta-analysis) have been published on RWE safety outcomes as a result of switching from the original reference medicine to a biosimilar, this manuscript is of particular relevance given the authors affiliation, US FDA, the origin of the data analysed - US sourced data of controlled trials- and the statistical approach undertaken.

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Reviewer #1: Yes: Fernando de Mora

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Safety outcomes when switching between biosimilars and reference biologics

 A systematic review and meta-analysis

PONE-D-23-17848R1

Dear Dr. Herndon,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Enrique Teran

Academic Editor

PLOS ONE