Evaluation of treatment efficacy in PBS/IC is challenging due to short duration of trials, heterogeneity of disease, and the lack of knowledge of the natural history of disease.
The RCTs we analyzed have not taken into consideration the variability of symptoms over time and regression to the mean. Most trials were short, with a mean duration of 15 weeks, which might not be optimal given the chronic nature of PBS/IC symptoms. As reflected in results from the largest observational IC study to date, the Interstitial Cystitis Database (ICDB)—patients who began with the most severe symptoms demonstrated the greatest initial improvement (i.e., their symptom scores moved toward the population mean).41
Conversely, patients who began with mild symptoms were more likely to worsen. Appropriately designed RCTs would have minimized such bias. Additionally, short duration of trials limits generalizability of findings.
Inadequate blinding (e.g., saline as placebo in DMSO trials32, 33
), small number of patients (e.g., PPS24–26
), and nonstandardized outcome measures (e.g., bladder biopsy findings42
) present additional challenges to analyzing treatment efficacy for PBS/IC. While most trials used the NIDDK diagnostic criteria for IC, very limited information was presented about participants who were ineligible or about symptomatic patients without bladder glomerulations (e.g. patients with painful bladder syndrome). It is well-known that strict use of NIDDK criteria would exclude 60% of patients with PBS/IC.6
Therefore, it is difficult to extrapolate how the findings from IC trials might relate to the larger majority of patients across the spectrum of PBS/IC symptoms.
The definition of symptoms—such as pain, urgency and frequency—varied considerably across the trials. Symptoms were measured using several different scales, making it inappropriate to pool the data for specific pharmacologic interventions investigated in more than one trial and also making it difficult to compare the findings in a qualitative synthesis. Consequently, it is not clear whether a positive result based on the pain scale of the OLS-SI, for example, is as good as, better than, or worse than a positive result on a different scale. Outcomes such as “global improvement,” in which participants were asked to rate themselves as better or worse than they were before the intervention began, were frequently reported. However, as has been shown to be the case with CFS and other chronic pain syndromes, the person may feel better able to cope with symptoms because they have reduced their expectations of what they should achieve, rather than because they have made any recovery as a result of the intervention. A more objective measure of the effect of any intervention would be whether participants have increased their working or waking hours, returned to work or school, or increased their physical or sexual activities.
The appropriate duration and follow-up of interventions used in the management of PBS/IC remains unknown. Given fluctuation of symptoms and the relapsing nature of PBS/IC we suggest that follow-up should continue for at least an additional 6 to 12 months after the intervention period has ended to confirm that any improvement observed was due to the intervention itself and not just to a naturally occurring fluctuation in the course of the illness or regression to the mean.
High dropout rates may be important indicators of the unacceptability of an intervention. This appears to be the case with cyclosporine,29
which had dropout rates of 55%, 19%, and 26%, respectively. High dropout rates may also indicate that the trial protocol is too rigid to accommodate any but a very specific group of participants, as might be the case with cyclosporine and DMSO. Again, this limits the generalizability of the findings.
Finally, many of the treatment response differences in IC clinical trials may be related to the heterogeneity of this illness. Identifying patient subsets based on response to specific treatments and biologic variables is one of the most challenging tasks in IC research. Patients with Hunner’s ulcer on cystoscopy form one such subgroup. This group, however, is relatively small since an ulcer is present in only about 15% of patients with IC. Hunner’s ulcer patients, therefore, should probably be enrolled as an isolated subset of IC patients.
Scant data are available from RCTs to confirm the efficacy of current pharmacological approaches to PBS/IC. What data do exist emerge from inadequately designed trials characterized by high dropout rates, restrictive protocols, variation in outcomes measures and definitional vagueness. Moreover, PBS/IC is a multifactorial and heterogeneous clinical symptom complex, yet RCTs designed to test pharmacologic agents have not taken into consideration the variability of symptoms over time or regression to the mean. Determining the optimal treatment strategy therefore remains elusive. Future treatments for PBS/IC will certainly be better informed by further unraveling the pathophysiologic mechanisms underlying the disease. Meanwhile, the key to developing evidence-based therapies is in establishing a consensus on standardized outcome measures and then designing and conducting appropriate RCTs that employ those standards.