Review for 10.1186/s12876-025-04154-w (2025)

Title: Safety of infliximab and adalimumab in pediatric inflammatory bowel diseases: a
disproportionality analysis from the FAERS database
Version: 0 Date: 25 May 2025
Reviewer's report:
This manuscript presents a large-scale pharmacovigilance analysis of infliximab (IFX) and
adalimumab (ADA) in pediatric IBD using the FAERS database, spanning two decades of
data. While the authors tackle a highly relevant topic with substantial clinical implications,
the manuscript is not currently suitable for publication in its present form due to several
major methodological limitations, a lack of critical interpretation, language deficiencies, and
unresolved statistical ambiguities.
The manuscript’s main strength lies in the large dataset and its clinical relevance—particularly
the comparative time-to-onset analysis and the characterization of infusion- and injection-related
reactions. The discussion also attempts to connect real-world findings with known adverse
events, which is important for translating pharmacovigilance data into practice.
However, there are substantial weaknesses that preclude acceptance:
Major Concerns:
1. Lack of Case Validation and Clinical Context: FAERS is a spontaneous reporting system,
but the authors treat the data as though it were derived from controlled clinical registries. There
is no clear effort to address duplicate or inconsistent reports beyond superficial deduplication
rules. Crucially, comorbidities, disease severity, prior treatments, and infection risk profiles are
unmeasured confounders and unaccounted for.
2. Methodological Rigor of Disproportionality Analysis: The authors rely exclusively on
ROR and PRR without sufficient justification for thresholds or sensitivity analyses. There
is no attempt to explore confounding due to concomitant medications or underlying disease
activity, nor are competing pharmacovigilance approaches (e.g., Bayesian methods or EBGM)
considered to triangulate signal strength.
3. Inconsistent Attribution of AEs: Many reported adverse events may reflect underlying IBD
manifestations (e.g., haematochezia, abdominal pain) or comorbidities, rather than drug-induced
effects. The manuscript fails to clearly distinguish signal causality versus disease-associated
symptoms, leading to potential misclassification of signals as drug-related.
4. Overstated Conclusions about Causality and Safety Profiles: The authors state that some
adverse events “were not listed in the product label” and then imply novel safety signals. This
is misleading, given that FAERS data cannot support causal inference or determine incidence.
The claims regarding psychiatric disorders, suicidality, and malignancy should be framed far
more cautiously, especially in a pediatric context.
5. Flawed Interpretation of Time-to-Onset Data: The TTO analysis is descriptive but lacks
comparative statistical testing, regression adjustment, or hazard modeling. The Weibull analysis
is briefly mentioned but poorly integrated and interpreted. Without accounting for follow-
up time or exposure duration, the conclusions drawn about timing patterns are limited and
potentially biased.
6. Supplementary Data Are Insufficiently Integrated: The supplementary tables are not
adequately referenced in the main text. Important values (e.g., SOC signal thresholds,
malignancy signal interpretation) are not contextualized for the reader, and discrepancies
between the tables and the narrative remain unaddressed.
Minor Concerns:
• The manuscript lacks clarity in terminology, frequently conflating terms such as “signal,”
“incidence,” and “risk.”
• Several sections are overly verbose, with redundant reiteration of results that could be
streamlined.
• The figure legends and tables require better annotation and should be referenced more precisely
in the discussion.
• The classification of adverse events, particularly for psychiatric and dermatological reactions,
appears overly broad and not consistently aligned with MedDRA PT standards.
Limitations Unacknowledged by Authors:
• The analysis does not differentiate between originator and biosimilar biologics, despite the
increasing clinical relevance of biosimilars in pediatric IBD.
• There is no assessment of reporting trends over time (e.g., post-approval peaks, media-triggered
spikes), which can heavily skew signal interpretation.
• No attempt is made to stratify by country, despite clear regional differences in reporting
behavior (e.g., consumer reports dominating ADA submissions).
• The differential impact of route of administration on AE detection (intravenous vs
subcutaneous) is underexplored and deserves methodological adjustment.
Language and Reference Revision:
The manuscript suffers from non-native phrasing, awkward sentence constructions, and
grammatical inconsistencies. There is a frequent misuse of plural/singular nouns (e.g.,
“pediatric IBD are”), articles (“the AEs”), and tense inconsistencies. Several statements lack
clear references or improperly cite numerical thresholds. The reference list is extensive but
occasionally redundant, and citation formatting needs to align with journal guidelines (e.g.,
avoid placing references at the end of sentences without integration).