Ricardo N. Werner

Background In dermatology, a medical speciality with a relatively high number of rare diseases, physicians often have to resort to off‐label treatment options. To avoid claims, physicians in Germany can file a cost‐coverage request (off‐label application, OL‐A). Objectives Our aim was to investigate the extent to which the current regulations affect patient care. Material and methods Prospective cohort study among tertiary dermatology clinics throughout Germany, consecutively including OL‐As (05/2019–09/2020) and assessing the follow‐up correspondence. We modelled regressions to assess factors associated with cost‐coverage decisions and the time needed by health insurers to process the OL‐As. Results Thirteen clinics provided data on 121 OL‐As, two of which applied for on‐label treatments. Of the remaining 119 OL‐As, 70 (58.8%) were immediately approved and 44 (37.0%) rejected. Including cases with one or more appeals, 87 of 119 OL‐As (73.1%) were finally approved and 26 (21.9%) rejected. There was an association of the final approval rate with (1) the class of medication/treatment, with approval rates being significantly lower for JAK inhibitors than for biologics (OR 0.16, 95%‐CI: 0.03–0.82); (2) German state, with approval rates being lower in eastern than in western states (OR 0.30, 95%‐CI 0.12–0.76); and (3) cost of the intervention (no linear trend). However, none of these predictors was significant in our multiple logistic regression models. The median health insurer's processing time (first response) was 29 days (IQR 22–38). Our analyses showed no evidence of an association with the predictors we assessed. In cases approved, the median time from the decision to file an OL‐A to the actual initiation of the treatment was 65.5 days (IQR 51–92). Conclusions Our study points to substantial delays and inequalities in the provision of timely health care for dermatological patients with rare diseases, often involving treatments for which there is no adequate approved therapy.

Background Melasma is a common dermatological condition. Although its relevance as a skin condition is primarily of a cosmetic nature, it may affect the patient’s wellbeing and quality of life. A broad range of treatment options is available, which makes it difficult to choose the most appropriate of those treatments. Objectives To summarize and critically appraise evidence from investigator-blinded randomized controlled trials (RCTs) on the efficacy and safety of self-applied topical interventions for melasma. Methods We systematically searched MEDLINE and the Cochrane CENTRAL trials database for RCTs on topical, self-administered interventions for patients diagnosed with melasma. Eligibility was limited to RCTs that explicitly stated in their methods section (i) how they generated the random allocation sequence, and (ii) that the study outcome assessor was blinded to the participants’ group allocation. Outcomes of interest included evaluator-assessed clinical scores (such as the Melasma Area and Severity Index), quality of life and patient-reported outcomes, as well as safety outcomes. The study findings were meta-analysed, pooling data from studies on the same comparisons, if this was possible. We assessed confidence in effect estimates using the GRADE approach. Results Our searches yielded 1078 hits. We included 36 studies reporting on 47 different comparisons of interventions. These included medical treatments such as ‘triple combination cream’ (TCC), over-the-counter cosmetic and herbal products, as well as sun creams covering different light spectra. Pooling data was possible for only two comparisons, topical tranexamic acid (TXA) vs. hydroquinone (HQ) and cysteamine vs. placebo. Direct comparisons were available for a variety of interventions; however, the reported outcomes varied greatly. Overall, our confidence in the effect estimates ranged from very low to high. Conclusions Our findings indicate that TCC and its individual components HQ and tretinoin are effective in lightening melasma. Besides these established self-applied treatment options, we identified further medical treatments as well as promising cosmetic and herbal product treatment approaches. Furthermore, evidence suggests that using broad-spectrum sunscreen covering both the visible and ultraviolet-light spectrum enhances the treatment efficacy of HQ. However, with mostly small RCTs comparing treatments directly using a broad range of outcomes, further research is needed to draw conclusions about which treatment is most effective. What is already known about this topic? Melasma is a common dermatological disease. Although it is primarily a cosmetic condition, it can severely affect the patient’s wellbeing and quality of life. Treatment options for melasma include a broad range of medical, cosmetic and herbal products. Given the large number of available interventions, it is difficult for clinicians and for patients to make informed decisions about which treatment to choose. What does this study add? We systematically assessed data from investigator-blinded randomized controlled trials of self-applied topical interventions. Our GRADE evaluations of confidence in the findings ranged from very low to high and may help clinicians and patients navig