Objective According to meta-analyses and practice guidelines, benzodiazepines are effective in the treatment of panic disorder.1,2 However, to date, no meta-analyses have incorporated data from unpublished trials. Among all benzodiazepines, alprazolam is the most widely prescribed and has the highest frequency of nonmedical use, abuse, and related harms in the US.3 This study examined reporting bias with the extended-release (XR) formulation of alprazolam by comparing its efficacy for panic disorder using trial results from the published literature and the US Food and Drug Administration (FDA).

Design There was no protocol for this study, and it was not registered. Medical and statistical reviews for alprazolam XR were downloaded from Drugs@FDA (https://www. accessdata.fda.gov/scripts/cder/daf/index.cfm); all phase 2 and 3 randomized, double-blind, placebo-controlled efficacy trials were identified; summary statistics on 5 primary outcome measures were extracted; and the FDA’s regulatory decision as to whether, for purposes of approval, the trial provided evidence of efficacy (statistical superiority to placebo on all primary outcomes) was also extracted. For each FDA-registered trial, the published literature was searched for matching publications using PubMed, bibliographies of review articles, and Google Scholar. The best match between FDA-registered trials and publications was based on drug name, comparator, dosage groups, sample size, duration, and investigator name. Summary data on the drug-placebo comparison and whether the publication conveyed that the drug was effective were extracted. Two meta-analyses were conducted—one based on the FDA review and the other based on the published literature—and their effect sizes were compared. Reporting bias was examined by comparing the following: (1) overall trial results (positive or not) according to the FDA vs corresponding publications and (2) effect size (Hedges’ g) using FDA data vs published data. Risk of bias was not assessed because the objective was not to assess bias in trial methods (internal validity) but rather bias in results reporting.

Results The FDA review showed that 5 trials were conducted, only 1 of which (20%) was positive and published (as positive). The remaining 4 studies failed to demonstrate efficacy. Of those, 2 were not published; for the other 2, the articles selectively reported positive, nonprimary, or post hoc outcomes. Thus, according to the published literature, 3 of 3 trials (100%) appeared to show positive results. Alprazolam’s overall effect size calculated using FDA data was 0.33 (95% CI, 0.07-0.59), while that based on published trial data was 0.47 (95% CI, 0.30-0.65), an increase of 0.14, or 42% (Figure 29).

Conclusions According to the results of this analysis, reporting bias has inflated the apparent efficacy of alprazolam XR, as previously found with other drug classes. Because this inflation alters the risk-benefit ratio, clinicians may wish to reconsider their prescribing practices with respect to this benzodiazepine. This study highlights the value of regulatory data to public health.

References

1. Stein MB, Goin MK, Pollack MH, et al. Practice Guideline for the Treatment of Patients With Panic Disorder. American Psychiatric Association; 2010.
2. Wilkinson G, Balestrieri M, Ruggeri M, Bellantuono C. Meta-analysis of double-blind placebo-controlled trials of antidepressants and benzodiazepines for patients with panic disorders. Psychol Med. 1991;21(4):991-998. doi:10.1017/ s0033291700029986
3. Ait-Daoud N, Hamby AS, Sharma S, Blevins D. A review of alprazolam use, misuse, and withdrawal. J Addict Med. 2018;12(1):4-10. doi:10.1097/adm.0000000000000350

Conflict of Interest Disclosures Rosa Y. Ahn-Horst reported no conflicts of interest. Erick H. Turner previously worked as a medical officer for the US Food and Drug Administration and reviewed applications submitted by pharmaceutical companies to determine whether they should be approved for US marketing. He has no financial interest in any pharmaceutical products, approved or otherwise.