To the editors

Clinical premarket trials evaluate efficacy and safety of a therapeutic compound in highly selected participant groups under closely monitored circumstances. In contrast, noninterventional studies (NIS) on marketed products are often considered inferior, but are nevertheless encouraged by authorities, especially in terms of safety of real-life patients.

Here, we analysed the tolerability and safety during the updosing phase of a house dust mite (HDM) subcutaneous allergen-specific immunotherapy (SCIT) [1, 2], marketed in Austria shortly before start of this study.

The open prospective NIS was conducted in Austria and ran in 7 centres from 2017 to 2019. After having given written informed consent, 32 eligible patients including 5 children (Online Resource 1) with allergic rhinitis (AR) with/without (+/−) asthma were treated with purified, modified and microcrystalline tyrosine (MCT)-adsorbed allergen extracts of HDM Dermatophagoides pteronyssinus and/or Dermatophagoides farinae. The study comprised 6 visits (V1–V6) including 4 visits during the short updosing phase (Online Resource 2). Patient characteristics (Online Resource 3), diagnosis of AR, symptoms and medication use (Online Resource 4) in the previous year as well as tolerability and medication use and symptoms after initiation of HDM-SCIT were evaluated.

Overall, no fatality nor serious adverse drug reaction (ADR) occurred during the study. No epinephrine was used. Four ADRs were reported in 3 adults (9.3%). One asthmatic patient with a mild to moderate recurrent airway obstruction classified as grade II systemic reaction discontinued the treatment. Swelling at the injection site (5–10 cm in diameter) occurred in 3 patients during the updosing phase: 1 reaction at 300 standard units (SU) and 2 at 900 SU. Tolerability was mainly rated ‘very good’ as assessed by the investigators and patients (Table 1).

Table 1 Tolerability of the treatment as assessed by the investigator and the patient
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All symptom scores were lower (by up to 56.3%) at V6 in comparison to the retrospective evaluation at V1 (Fig. 1). The individual symptoms ‘sneezing’ and ‘nasal obstruction’ improved the most (Fig. 1, Online Resource 5). Symptomatic medication use was also substantially reduced (Online Resource 6).

Fig. 1
figure 1

Symptom scores from visit 1 (V1) to visit 6 (V6). The rhinitis, conjunctivitis and asthma scores (1–7 points), combining symptom severity and symptom frequency, were assessed retrospectively at visit 1 (N = 31, N = 10, N = 11, respectively) and after the updosing phase (subcutaneous allergen-specific immunotherapy [SCIT] initiation) at V6 (N = 18, N = 6, N = 6, respectively). The data are presented as mean + standard deviation (SD), ***p = 0.002 (a). The reduction was even more pronounced when comparing patients who had evaluations at V1 and V6 (N = 18, N = 5, N = 5, respectively), with −34.1% for rhinitis, −50.0% for conjunctivitis and −56.3% for asthma symptoms. The severity of the pronounced nasal symptoms in house dust mite (HDM) allergy, rhinorrhoea and nasal obstruction (0–3), were significantly reduced after updosing phase (V6–V1, mean + SD): Rhinitis score −0.57 + 1.237; Nasal obstruction −0.78 + 1.126; **p ≤ 0.005 (b). For children, the improvement in the clinical parameters was even more pronounced (V6–V1, mean + SD): Rhinitis score: −2.00 + 1.414; Nasal obstruction: (−1.00 + 1.000), however, due to the small number of patients these results could not reach significance (c). ns not significant

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Here, we show that the HDM-SCIT is safe and well tolerated during the updosing phase in the scope of standard medical care. ADRs occurred after 2.6% of all injections, which is in line with data from a recent meta-analysis on SCIT [3]. However, of the originally planned 100 participants only 32 patients were included in this study due to an unexpectedly low participation rate of the study centres. The main barrier holding off investigators from participating was the administrative work load to fulfil requirements of the Vienna ethics committee which was comparable to clinical trials.

At the same time, the conduct of NIS is encouraged by regulatory authorities and the community, to demonstrate the clinical use of marketed products in unselected real-life patients. In practice, however, the bar is set so high that the efforts required to participate in a NIS is almost similar to those required for a clinical trial. Hence, only physicians who are experienced in clinical trials and are therefore not afraid of the administrative burden of such a study, are willing to participate. Moreover, the general negative image of NIS also prevented us from reaching the targeted number of included patients.

Despite the low inclusion figures, clinical effects on allergic symptoms were already detected that are comparable to a recent study presenting data after 2 years of treatment [4]. The use of symptomatic medication was also considerably reduced.

In conclusion, the modified and MCT-adsorbed HDM-SCIT showed no elevated application risk during updosing in conjunction with favourable clinical effects in the majority of patients. Since NIS can represent a cross-section of real-life patients, it should be considered complementary to clinical trials, and therefore, common acceptance and feasibility of conducting NIS would be desirable.