Letter to Editor: Oral Isotretinoin in Recalcitrant Facial Flat Warts—Methodological and Reporting Gaps Undermine Generalizability

We read with great interest the recent randomized controlled trial by Olguín-García et al., which evaluated the impact of two doses of oral isotretinoin on recalcitrant facial flat warts and associated psychosocial outcomes in adult patients [1]. The authors should be commended for addressing a clinically relevant dermatologic condition that is often resistant to standard therapies. However, several methodological limitations merit consideration.

Firstly, the study was terminated early due to an interim analysis, yet there was no mention of a pre-specified stopping rule or alpha adjustment. This omission increases the risk of type I error and could inflate the observed treatment effect. Unlike other robust RCTs such as the multicenter trial by Ramanan et al., which followed predefined protocols without early stopping, the current trial lacks transparency in its interim analysis plan, undermining the credibility of its conclusions [2].

Secondly, the absence of a placebo or active comparator group restricts the ability to attribute observed improvements solely to isotretinoin. Donnez et al. in the EDELWEISS 3 trial, incorporated a placebo control and double-dummy design, enabling clearer interpretation of treatment effects while minimizing placebo-related confounding—a critical element when evaluating conditions prone to spontaneous resolution [3].

Thirdly, the single-center nature of the trial limits external validity. The study population was drawn exclusively from a dermatology clinic in Mexico City, without stratification for demographic or geographic variables. In contrast, Eng et al. enhanced generalizability in their malaria RCT by accounting for regional and host-related confounders through relocation and stratification strategies [4].

Moreover, adherence was assessed solely via pill count, which is a subjective and often inflated measure. There were no efforts to corroborate adherence with biochemical monitoring or digital tracking. This parallels concerns raised by Gordon et al. in their Cochrane review, where missing data on implementation metrics like adverse event-related withdrawals compromised the interpretability of multiple RCTs [5].

In conclusion, while the study by Olguín-García et al. provides encouraging data on isotretinoin's efficacy in treating recalcitrant flat warts, the methodological concerns—including lack of placebo control, single-center design, subjective adherence monitoring, and unclear interim analysis practices—limit the strength of its conclusions. Future trials should address these issues by implementing rigorous design standards to improve validity and reproducibility.

Ruba Javed: conceptualization, methodology, software, writing – original draft, writing – review and editing. Javed Iqbal: conceptualization, methodology, writing – original draft, writing – review and editing.

The authors have nothing to report.

The authors declare no conflicts of interest.