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Data from clinical trials investigating on-demand medication often consist of an intentionally varying number of measurements per patient. These measurements are often observations of discrete events of when the medication was taken, including for example data on symptom severity. In addition to the varying number of observations between patients, the data have another important feature: they are characterized by a hierarchical structure in which the events are nested within patients. Traditionally, the observed events of patients are aggregated into means and subsequently analyzed using, for example, a repeated measures ANOVA. This procedure has drawbacks. One drawback is that these patient means have different standard errors, first, because the variance of the underlying events differs between patients and second, because the number of events per patient differs. In this paper, we argue that such data should be analyzed by applying a multilevel analysis using the individual observed events as separate nested observations. Such a multilevel approach handles this drawback and it also enables the examination of varying drug effects acrosspatients by estimating random effects. We show how multilevel analyses can be applied to on-demand medication data from a clinical trial investigating the efficacy of a drug for women with low sexual desire. We also explore linear and quadratic time effects that can only be performed when the individual events are considered as separate observations and we discuss several important statistical topics relevant for multilevel modeling. Taken together, the use of a multilevel approach considering events as nested observations in these types of data is advocated as it is more valid and provides more information than other(traditional) methods.

Background Efficacy of on-demand drugs for women with hypoactive sexual desire disorder or female sexual interest/arousal disorder (FSIAD) should be assessed using a validated instrument that assesses the discrete sexual events during which the on-demand drug is taken, because this type of assessment is more proximate to an on-demand drug's efficacy compared to instruments that assess sexual function over longer periods of time. Aim The aim of this study was to assess the psychometric properties of the Dutch translation of the previously validated 11-item Sexual Event Diary (SED) for measuring sexual satisfaction and sexual functioning during discrete sexual events. Methods Psychometric assessment was performed on data of 1,840 SEDs from 139 women with hypoactive sexual desire disorder/FSIAD, collected during a randomized clinical cross-over trial conducted in the Netherlands. Outcomes Item scores of the SED at the event level, and at subject level, summarized item scores during the placebo run-in period (PRI) and active treatment period, and score changes from PRI to active treatment period. Results Reliability and convergent validity were confirmed. All item scores showed the ability to discriminate between known groups. Larger mean score changes from PRI were observed in groups with known benefit from the medication, as compared to those with no benefit. Guyatt effect sizes ranged from 0.51–1.02, thereby demonstrating ability to detect change. Clinical Translation The Dutch version of the SED is an excellent instrument for assessing female sexual functioning and sexual satisfaction during discrete sexual events and for assessing these concepts over longer periods of time. Conclusions Data were collected in a randomized, well-controlled trial. The large number of data points gave high statistical power, and the results confirmed previous findings. However, care is needed when generalizing the SED's validity to other areas of research, eg, recreational drug use and sexual risky behaviors, since the current validation study has not used such data. Consistent with the US-English version, the Dutch version of the SED is a reliable, valid, and responsive instrument, and suitable for use in evaluating effects of on-demand drugs in women with FSIAD.

Low sexual desire is the most common sexual complaint in women. As a result, many women suffer from sexual dissatisfaction which often negatively interferes with their quality of life. These complaints have been classified as the condition Hypoactive Sexual Desire Disorder (HSDD), and have recently been merged with the condition Female Sexual Arousal Disorder (FSAD) into the diagnosis Female Sexual Interest/Arousal Disorder (FSIAD) in the DSM-5. To date, no drug treatment approved by the U.S. Food & Drug Administration (FDA)/European Medicines Agency (EMA) is available to treat women with HSDD/FSIAD. As a result, there is an unmet need for a drug treatment for HSDD/FSIAD. In our search for an adequate treatment we followed a different approach compared to other pharmaceutical companies. Based on a personalized sexual medicine approach we proposed that different mechanisms cause low sexual desire in women, namely an insensitive system for sexual cues or dysfunctional activation of sexual inhibitory mechanisms. Subsequently we developed two new on-demand drug treatments for women with HSDD/FSIAD based on these different causal mechanisms. One treatment (testosterone combined with a phosphodiesterase type 5 inhibitor) has been developed for women with HSDD/FSIAD due to a relatively insensitive system for sexual cues, while the second treatment (testosterone combined with a 5-HT₁A receptor agonist) has been developed for women with HSDD/FSIAD due to dysfunctional activation of sexual inhibitory mechanisms.