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Since the inception of this column, I have studiously avoided an analysis of the pharmaceutical industry's attitude to interstitial cystitis (IC). There are several explanations for this apparent omission on my part, ranging from: the belief that there is relatively poor commercial opportunity; it is impossible to accurately design regulatory standard clinical trials; and that I know nothing about the subject. As the latter has never previously stopped me I will examine the other possibilities.

IC is a chronic syndrome characterised by bladder and pelvic pain and/or pressure, and increased urinary frequency and urgency in the absence of any identifiable cause, e.g. bacterial infection. The aetiology and pathophysiology of IC remain unclear and there are neither well-defined diagnostic criteria for the condition or universally effective treatments. Not a great enticement to the pharmaceutical industry, you might say.

A diagnosis of IC is usually reached by excluding other possible causes of pain and urinary symptoms, and consequently diagnosis may not be reached for several years after the first presentation. In the interim, women may undergo unnecessary hysterectomies or treatment for endometriosis, without gaining symptomatic relief.

The absence of a definitive diagnostic test and standard clinical criteria gives rise to substantial differences in national prevalence estimates for IC. There is an epidemiological consensus that IC is far more common in woman than men and is more prevalent in white woman than in those of other races (although a similar prevalence has been reported in Hispanics), being most often diagnosed in woman in their mid-40s. Depending on which diagnostic criteria are applied, reported estimates of the USA prevalence rate range from up to 70 cases per 100 000 (NIDDK clinical criteria) to 2.6 cases per 100 000 (based on strict pathological criteria). Applying this upper prevalence value to the female population in the USA returns an estimate of only 72 000 sufferers.

A survey of self-reported IC diagnoses/painful bladder syndrome conducted within the Center for Disease Control's National Health and Nutrition Examination Surveys (NHANES), involving a very large sample of American households, indicated that the self-reported IC rate has not significantly changed since 1989 and remains at about 1 in 120 women (and only 1 in 1700 men).

In the absence of effective treatments, IC is usually managed in an escalating fashion, starting with dietary changes, fluid management and behavioural modification, and progressing to treatment with one of the two currently FDA-approved agents (pentosan polysulphate sodium, Elmiron or generic DMSO, RimSo-50) and/or off label use of antihistamines, analgesics, antidepressants, anti-inflammatory drugs or ‘mystery mechanism’ agents such as heparin (and the indeed aforementioned DMSO and pentosan polysulphate sodium).

Transcutaneous electrical nerve stimulation (TENS) units, intravaginal electrical stimulation and acupuncture have been beneficial in some sufferers. The antimuscarinic agents oxybutynin and tolterodine may be used to treat urinary urge but can also be counterproductive, as they can impair bladder emptying and exacerbate pain.

In summary, current pharmacological treatments are relatively few and represent a miscellany of ‘approved’ and off-label agents. Available intravesicular instillation treatments have limited, if any, evidence for clinical efficacy. Even with the credentials of the most widely used agent pentosan polysulphate sodium (Elmiron), the clinical evidence-base from placebo-controlled trials is somewhat lacking.

In addition, there are few new therapies in development for IC. These include the vitamin D3 analogue, BXL 628 (BioXell) which is claimed to act by stabilising mast cells and is in Phase II clinical development, and a Phase III study on BCG (Bioniche) is about to start. BCG is claimed by the developers to down-regulate the inflammatory response in the bladder. Other companies known to be active in the area include Urigen and Plethora Solutions Ltd., with infused alkalinised agents designed to increase transcutaneous absorption.

When the epidemiology data are coupled with this relative absence of drugs, there would appear to be a relatively large unmet medical need and a corresponding commercial opportunity, and if a wider claim could be achieved, (e.g. to include chronic pelvic pain) the magnitude of the commercial opportunity increases dramatically. If we assume this is the case (which may be an unreasonable assumption) any lack of interest on behalf of the pharmaceutical industry would have to arise from other factors. Once again we must return to the diagnostic criteria and clinical definition as being the nub of the problem.

In essence, IC represents a symptom complex involving the algebraic summation of many different factors which can either be dependent or independent, and with symptoms that can wax and wane. In addition, IC is almost invariably a diagnosis by exclusion. All of these factors result in the situation that realistic clinical trials are incredibly difficult to design and in many ways the situation is analogous to that for another symptom complex, irritable bowel syndrome (IBS). Although several large-scale clinical trials in IBS have been conducted, no drug is widely approved or used. In the absence of any globally approved products, there is no guaranteed regulatory route, i.e. one that, if followed will with a high degree of certainty result in marketing approval. However, if pain were to be used as a primary endpoint, proof-of-concept phase II studies would be relatively straightforward to design. This brings me to my final point; what concept or mechanism is likely to translate into clinical benefit?

In addition, virtually nothing is known about the pathophysiology of IC. Although the analogy with IBS for the degree of difficulty in the design of clinical trials is highlighted above, the situation is actually much worse. At least in the case of IBS there were several potential mechanistic starting points, e.g. antimuscarinic (darifenacin, Enablex) or serotonergic (alosetron, Lotronex) mechanisms. In the case of IC, as the pathophysiology is even less well defined, the mechanistic starting points are much more ethereal. In many ways we might be as well to consider gene therapy as a starting point [1].

Next month I will examine the potential opportunity in the other ‘Cinderella’ urological disorder, prostatitis.