Time to free the shackles?

Mike G. Wyllie, Global Pharma Consulting Ltd, 61 Abbey Street, Faversham, Kent, ME13 7BN, UK. e-mail: m.wyllie@globalpharma.co.uk

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With the advent of ‘the fourth of July’ it is timely to view the attitude of the regulatory authorities, within that context, towards the development of urological drugs by the pharmaceutical industry? Particularly relevant is the section that ‘all men are created equal, that they are endowed . . . with certain unalienable Rights, that among these are Life, Liberty and the pursuit of Happiness’. It would almost seem to sufferers that there is a caveat ‘unless you happen to have stress incontinence, premature ejaculation (PE), or interstitial cystitis (IC)’.

Am I seriously advocating that the USA government is ‘urology-patient-phobic’? As someone entering the USA on a monthly basis, you are correct, and I am sure that most senators and congressmen do not even think about urological disease until, like Bob Dole, they become part of an advertising claim. However, ultimately the government is responsible for having established the Food and Drug Administration (FDA). Given the history of pharmaceutical drug development before the FDA, no one can argue that by and large, and certainly in the early years, it has done a good job of ensuring that drugs with appropriate benefit : risk ratios have reached the American consumer. However, more recently there is an impression that the agency have become increasingly conservative. To let the reader decide whether there has been a change in the FDA’s stance, I will examine two scenarios involving urological drugs before and after 1990. Although there are many potential comparisons, only the situations in BPH and sexual health will be examined.

In the ‘good old days’ the arrival of doxazosin and terazosin was accompanied by a database of 2–300 patients and usually one primary endpoint, e.g. the IPSS and sometimes one question relating to overall satisfaction. In general, drugs could be approved with little evidence of ‘normalisation’ of symptoms and relatively modest safety databases. The most recent arrival on the market, alfuzosin, has had to be accompanied by two co-primary indices of efficacy and disease-specific quality of life (QoL) and a plethora of cardiovascular evaluations. However, overall, it is only a change in the magnitude of data that has been required rather than a much broader range of data.

In erectile dysfunction (ED) the situation is essentially similar. All that was required for tadalafil and vardenafil was ‘sildenafil-type’ data, but Lilly and Bayer would argue much, much more of it. This was also the period when the Agencies (not just in the USA) were demanding not only more data but also different types of data. In most situations they were demanding that instead of statistical significance being shown against one endpoint being satisfactory, that improvement versus the co-primary endpoint was required. In the case of ED three co-primaries are having to be used. As any statistician (irrespective of being worth their money or not) will tell you, this has a considerable impact on the powering of the study (and obviously cost).

Perhaps not surprisingly, given the origin of some of the scoring systems used, the FDA has become increasingly wary of the value of some of them. Knowing the history of the IPSS and being around at the time of the development of the International Index of Erectile Function (IIEF), I can understand that concern. Every company appeared to have its own preferred scoring system, which had little commonality with their competitors. At one stage, the pharmaceutical industry was trying to copyright these, thus controlling the use (by competitors) of their instrument; a good instrument became the one mandated by the regulatory authorities. However, the spectre of ‘anti-trust’ seems to have put paid to this approach by industry and (hopefully unsuccessful) attempts at copyrighting seems to be restricted to academics.

Most of the above requirements are logical and indeed to be applauded, but there is a down-side, i.e. cost. Not since the days of the IPSS has it been possible to get your friends together and create a questionnaire; the FDA now requires it to be ‘validated’ and very helpfully lay down guidelines on the validation process on their website. Adherence to these guidelines is likely to cost a company entering a new arena ≈$20 million for a validated questionnaire. The use of the word ‘questionnaire’ obviously does not do justice to the quality of the information to be captured. Not unreasonably, the FDA is interested in the benefit to the patient and hence a more accurate descriptor is a patient-reported outcome (PRO) that will incorporate questions relating to disease-specific QoL. There is as yet no requirement for a validated PRO in the European Union; apart from this bifurcation, generally regulatory authorities in most countries are aligned in their requirements for urological drug development.

The major obstacle for drug development in a new (i.e. previously untreated) urological disease, e.g. PE or IC, is that of disease definition. Quite rightly, although some medical reviewers are keen to get involved, the FDA is not in the business of disease definition. Once you have a disease definition and a validated PRO they will then help to define an appropriate clinical response. This is easy in an established disease such as ED where the PRO (albeit the incompletely validated IIEF) in essence becomes part of the definition and/or diagnostic.

In PE or IC, where do you start, as there is also a requirement that that the definition has to be evidence-based? In the case of PE a definition was recently devised by consensus by the ‘wise men and women’ of the International Society of Sexual medicine (ISSM) [1]. Fortunately for the ISSM, there was a considerable amount of normative and patient data already published that could be used to formulate the definition of the disease. In the case of IC the basis for disease definition is less immediately obvious.

As can been seen from the above, entry into new urological disease areas is becoming increasingly difficult for the pharmaceutical industry. The development of a validated PRO could take 2–3 years and cost £20 million. The cost compared to the overall drug development cost is not the issue, but the extra time to market could be. The situation in IC is particularly problematical; unless the FDA helps to determine an appropriate group to define the condition, and accept a relaxation of ‘evidence-based’ to ‘based on the best evidence available’, there is little hope for the hundreds of thousands of sufferers.

To return to and paraphrase the declaration of independence ‘when the government fails to protect these rights, it is not only the right but also the duty of the patients to overthrow the government’. In the eyes of the highly effective IC lobbyists, perhaps the government and FDA are synonymous.