Software Changes and Technical Failures in Clinical Trials of Digital Interventions Used Alongside Pharmacotherapy: Narrative Review of Regulatory Guidance and Published Evidence

Background/Objectives: Software changes and technical failures can alter the treatment delivered by a digital intervention or the data used to evaluate it. In trials alongside pharmacotherapy, medication use and replacement care may also affect the comparison. This review examined which functions software events affected and whether the available evidence supported the intended treatment comparison. Methods: A focused narrative review combined 22 public guidance and related documents, two product records, and 67 academic publications selected from PubMed searches completed on 10 September 2026. Cases were compared by the function involved, reported response, and information needed to assess remaining uncertainty. Results: CureApp’s assessment found no health effects from reported malfunctions but did not quantify interrupted treatment or lost endpoint observations. Spark incorporated software version into pooled analyses but did not report separate treatment effects for each version. In Quitting Matters, incomplete recording affected a primary engagement outcome, and retaining partial records did not establish comparable capture between groups. These examples distinguish evidence that an event occurred, evidence that it was addressed, and evidence about its effect on the comparison. They do not estimate the frequency of software events or their causal effects on efficacy. Conclusions: Appraisal requires assessment of both intervention integrity and data integrity. Investigators should link affected functions and event periods to treatment delivery, medication use, replacement care, and outcome records, then evaluate whether the analysis addresses the intended comparison. Repair or absence of observed harm alone cannot establish that the intended treatment comparison remains supported.