Is soliciting adverse events appropriate for sublingual immunotherapy trials?

Published online: February 9, 2018

Adverse event (AE) reporting is critical for the development and approval of new drugs. Several methods of collecting AE data exist, including general, open-ended questioning of the patient by the investigator without specifying any particular AE (unsolicited collection) or structured questionnaires that ask about the presence/absence of specific AEs (solicited collection). Unsolicited AE data collection is simple and cost-effective but may lead to underreporting of AEs. Solicited AE data collection may enhance detection of a safety signal but may lead to inflated AE frequencies due to a suggestive effect. Solicited AE collection has recently been requested by the US Food and Drug Administration for sublingual immunotherapy (SLIT) tablet trials.

Recently in The Journal of Allergy and Clinical Immunology: In Practice, Nolte and colleagues compared the safety profile of the SQ house dust mite (HDM) SLIT-tablet from clinical trials that collected AE data using unsolicited or solicited methods. Four phase 2 and phase 3 randomized, double-blinded, placebo-controlled trials of HDM SLIT-tablets were conducted where patients received daily SQ HDM SLIT-tablet or placebo. In 3 of these trials, AE collection was unsolicited (e.g., general questioning by investigator) and the data for the 12 SQ-HDM dose was pooled (N=1287). In the fourth trial, in addition to general questioning by the investigator, reporting of local application site reactions was solicited daily in a structured questionnaire for approximately the first 28 days of treatment using closed-ended questions regarding specific local application site reactions identified by the World Allergy Organization (N=1272).

Overall, the type and category of AEs were similar between the trials with unsolicited AEs versus the trial that solicited AEs. Most AEs were local application site reactions, with the most common being throat irritation and oral itching. The percentage of patients treated with 12 SQ-HDM who discontinued due to AEs was 7.7% is the unsolicited AE trials and 9.8% in the solicited AE trial. Approximately 95% of the AEs related to treatment were mild-to-moderate regardless of the method of AE collection. However, the frequencies of many local application site reactions were notably higher in the solicited AE trial versus the unsolicited AE trials in the 12 SQ-HDM group (i.e., 68% vs 15%, respectively, for throat irritation and 62% vs 20% for oral itching) and in the placebo group (i.e., 22% vs 3%, respectively for throat irritation and 15% vs 3% for oral itching). Further study indicated that the higher frequencies of a few of the AEs (e.g., mouth and tongue ulceration) that were reported at ≤0.2% in trials for other SLIT-tablets may have been due to misinterpretation of the questionnaire by the subject.

The safety profile of SQ HDM SLIT-tablet was qualitatively unchanged by the method of AE collection, but frequencies of specifically collected AEs were higher when AEs were solicited versus unsolicited. Therefore, soliciting AEs did not appear to enhance safety signal detection. Rather, the higher frequencies observed in the placebo group with AE solicitation indicated that potential bias was introduced by leading questions that suggested to the patient that a specific AE may occur. Based on the current analysis, the authors suggest that AEs in SLIT-trials be collected by open-ended questioning without specifying individual AEs, although solicited AE collection may be beneficial for other products.

The Journal of Allergy and Clinical Immunology: In Practice is an official journal of the AAAAI, focusing on practical information for the practicing clinician.

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