Clinical trials for aspiring dummies (and urologists)

M.G. Wyllie, Urodoc Ltd, Maryland, Ridgeway Road, Herne, Kent, CT6 7LN, UK. e-mail:

Over the last few years there has been a major decrease in the volume of clinical trials work in urology and andrology. Gone are the years of plenty in BPH, overactive bladder and erectile dysfunction (ED). Stress incontinence work has not really taken off, apart from trial activity with duloxetine and premature ejaculation (PE), languishing with the slowing of approval for dapoxetine. Few new large-scale studies are anticipated in prostate cancer and interstitial cystitis. There has also been a major ‘paradigm shift’ by the regulators, in that they are requiring more data, but in general directed towards characterising product safety and not primary efficacy. As a result there have been many major players of previous years de-emphasising (albeit for differing reasons) urological research, including Abbott, Alza, Bayer, GSK, J&J, Roche and Pfizer. We are also leaving the era of affiliate-sponsored clinical trials to cultivate Key Opinion Leaders (KOLs) and ‘seed markets’. So, assuming I am interested in doing clinical trials, what can I do to make myself indispensable, i.e. not fly to conferences in the rear of the plane, you might be wondering.

The emphasis for industry has now moved towards getting ‘go or no-go’ answers at an earlier stage than previously. The rationale is that if your product is going to fail, you want that to happen at the earliest possible phase of clinical development. Shareholders dislike hearing bad news, but particularly if it is late-stage and expensive bad news. If you are particularly lucky at the time of failure, the ‘spin doctors’ can de-emphasise the importance of the product to your portfolio. There is now greater risk aversion by shareholders (at least with respect to their investment). When this is coupled to the paranoia of the regulatory authorities, many of the early-stage decision points are increasingly based on the assessment of safety, particular in the cardiovascular system.

The ability to undertake ambulatory haemodynamic assessments, coupled with orthostatic measurements, is in vogue, as is the measurement of QT interval (and the associated mathematical derivations). This is particularly relevant in product development for stress incontinence; sympathomimetic agents have long been shown to have some degree of benefit, but produce utility-limiting changes (blood pressure elevation) in the cardiovascular system. The two companies still heavily involved in this area, with the development of urethral selective α-agonists, directed most of their initial clinical development towards cardiovascular profiling, rather than assessing efficacy. Likewise, most of the companies still involved in the development of selective serotonin re-uptake inhibitors are showing particular interest in the propensity of these agents to produce orthostatic hypotension/syncope. It would also be prudent for companies developing ‘fast onset of action’ (nasal or inhaled) versions of apomorphine, presumably for ED, to set great store on the demonstration of a benign cardiovascular profile as a major criterion for onward clinical development.

The good news for all potential clinical triallists is that all of the above cardiovascular measurements are easy to make (certainly in relation to persuading patients to have repeat measurements of urodynamics via indwelling catheters or to participate in a RigiScan study). Indeed, members of the urological profession have long been at the forefront of cardiovascular haemodynamic assessment (c.f. Roger Kirby and Steve Kaplan in assessing hypotension with α-blockers, and Wallace Dinsmore in the original sildenafil nitrate interaction study). Not all basic measurements of cardiovascular variables require the input of men like Bob Kloner and Graham Jackson. However, input from the cardiologist is essential in defining the overall cardiovascular risk of any new drug or procedure.

In terms of efficacy, the type of study that industry might be developing is one that would not necessarily be considered outside the company to be ‘gold standard’. For internal decision-making a proof-of-concept study does not have to be double-blind nor even placebo-controlled. Industry has always undertaken this type of pilot study, but in times of plenty would often run a more conventional phase II programme in parallel. With budget restrictions and questioning of the return of investment from urological drug development there are already more of these studies. In general these are single-centre studies in eight to 12 patients or volunteers, and might only involve one administration and assessment of efficacy via a clinical surrogate endpoint. A study at a single centre undoubtedly reduces the variability, although obviously not reflecting real-life experience. I think the publication of many investigator-led protocols questions the definition of real-life, as I thought I knew it!

Viable surrogate endpoints are those that give an early-stage index of efficacy. Although patients present with symptoms, effective drugs for BPH produce single-dose urodynamic (Qmax) effects [1]. Rather than wait for changes in the IPSS that are not apparent for several weeks, companies are increasingly basing decisions on Qmax. An analogous situation is the use of RigiScan in ED rather than the International Index of Erectile Function and the Sexual Assessment Monitor [2] in product development for PE.

Overall therefore, there is likely to be an increasing emphasis by the pharmaceutical industry on discrete studies in relatively few patients. In reality, industry has always conducted these studies, but more decisions on onward clinical development will be based on the outcomes. This will undoubtedly have an impact on the amount of clinical trial work that will be directed towards investigators who are proven to be good recruiters. As is already happening, the trials will be designed within the pharmaceutical industry with input limited to one or two urological advisers.

In the medium term in urology and andrology there will be fewer large-scale phase III and marketing studies. Although these are likely to require several hundred or indeed a few thousand patients, these are likely to be powered toward addressing safety issues. As above, the key to completing the studies will be involving centres with high and proven recruitment rates. It is actually quite expensive to open a study centre even if it recruits no patients.

As well as having a clinical database on efficacy and safety, the pharmaceutical industry also has a database on trial recruitment. They know who you are! Greater importance is now being attached on recruitment rather than purely on cultivating KOLs.

As a potential clinical triallist, what does the above tell me? In the short-term there will be relatively few new large-scale (phase IIb/III) urological/andrological trials initiated. In the earlier-stage clinical development, most of the work will be directed towards specialist centres that can evaluate efficacy and safety (particularly cardiovascular) in relatively few patients.