Are we ‘normal’?


Mike G. Wyllie, Global Pharma Consulting Ltd, PO Box189, Sandwich, Kent, CT13 3AB, UK.
e-mail: m.wyllie@globalpharma.co.uk

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The arrival of dapoxetine into several European Union (EU) countries has once again raised the issue of what we mean by normality in the context of sexual function in the eyes of not just the regulators but also patients and physicians; the ancillary question is whether the pharmaceutical industry really cares.

In the case of erectile dysfunction (ED) the acceptable (in the eyes of regulators) use of a validated patient-reported outcome (PRO) such as the International Index of Erectile Function (IIEF) has been extended into a wider ‘diagnostic role’. Post hoc analysis has shown that the score of the IIEF, or variants thereof, can be used to define ED as ‘mild’, ‘moderate’ and ‘severe’ or ‘none’; the latter category being presumably ‘normal’. The use of the retro-scope in urological diagnosis has become common practice since the discovery, several years after widespread use, that 3 units change on the International Prostate Symptom Score (IPSS) is clinically relevant.

In ED and now presumably premature ejaculation (PE), we have a means of diagnosis; the assumption is that the regulators require for approval an acceptable disease definition, which in turn implies some degree of diagnosis to ensure that the inclusion and exclusion criteria for the clinical trial patient population have that disease. This would certainly be the case of the EU where dapoxetine has led the charge but is less of a fait accompli in the USA where the Food and Drug Administration (FDA) have not granted marketing authorisation. It would appear that the FDA may be on the cusp of accepting the Index of Premature Ejaculation (IPE) as a validated PRO. Should this be the case, the IPE has the potential (cf. the IIEF) for transformation from outcome to diagnostic instrument.

Up to the regulatory approval point in the drug development cycle you could reasonably assume that the pharmaceutical industry and the healthcare environment (the cost containers) interests in disease definition and diagnosis would be reasonably aligned; although it could be argued that the latter would be quite keen that there was no diagnosis or disease definition, as no drugs would be approved for that indication (the ultimate in short-term cost containment!). Subsequent to approval, you can imagine that the aspirations would be reversed with the healthcare gatekeepers wanting precise definition and diagnosis whereas the pharmaceutical industry could benefit from less precise definition.

In this context it has been calculated that over half the prescriptions for tadalafil (Cialis®) and sildenafil (Viagra®) are to ‘patients’ who based on IIEF definition do not have ED. Either there is a considerable use of these phosphodiesterase inhibitors (PDEi) in alternative indications, both approved (pulmonary hypertension) and unapproved (athletic performance enhancement), or there is widespread use in individuals wishing to enhance their normal sexual performance. Obviously, the pharmaceutical industry cannot condone such ‘off-label’ use of these drugs, yet they fall short of condemning the practice. After all, is that not what the concept of use under physician direction and/or compassionate use is about? Many a pharmaceutical company’s profit and thereby shareholder dividend has been enhanced by such prescribing habits and I am sure many would want it to continue. On a more serious note, it was such ‘off-label’ or compassionate use of PDEi in pulmonary hypertension that originally (i.e. pre-marketing authorisation) enabled many lives to be saved.

Of greatest contemporary relevance is the agreed definition of PE by the wise men and women of the International Society of Sexual Medicine (ISSM) [1]. Encrypted within the definition is an exchange of bodily fluids in ≤1 min, which causes some level of personal (or partnorial) distress and a negative impact on sexual quality of life. So now, we have a definition that should help with regulatory approval. How will that help with the diagnosis that will presumably precede the prescription of any medication?

In the ‘good old Viagra launch days’, the pharmaceutical industry (i.e. Pfizer) expended considerable effort in developing patient- and partner-friendly diagnostic instruments in ED. The actuality, rather than revisionism, is that a few dollars were spent on revamping the IIEF into shorter forms that did not outlast the attention span of either patient or the allocated few minutes of primary-care physician consultation time. In ED, this approach to diagnosis was accepted on a somewhat qualitative diagnostic descriptor of a ‘consistent inability to sustain an erection for sexual intercourse’. The situation in PE is theoretically compounded by the introduction of a quantitative element namely ‘. . . is a male sexual dysfunction characterised by ejaculation which always or nearly always occurs prior to or within about 1 min of vaginal penetration . . .’ . Most of us are challenged to know what our blood pressure is or even what our height and weight are. What is the probability that we know what our intravaginal ejaculatory latency time (IELT) is? Assuming there is now a reason to care what it is, how many of us would know how to record it? According to clinical trials protocols this is easily done using a stopwatch held by a partner or other participant. For protocol adherence (or should that be compliance), a detailed understanding of the Kama Sutra may also be a benefit in the ability to record start and stop (or should it be on and off?).

Now armed with our IELT, we now have to satisfy the distress quotient of the ISSM definition. In most countries, the ≈3 months wait to see a primary-care physician who is prepared to discuss PE will ensure that we are well into the distress scale; to be then told that we have in fact to have four IELTs before prescription should take us ‘over the top’! The scenario described above is much like suggesting that all patients with de novo ED should have their erectile function quantified based on RigiScan® measurements to assess nocturnal penile tumescence before prescribing. Although as the manufacturer of RigiScan, I would applaud this suggestion, I would imagine it would not become de rigueur.

In PE, I am sure consumer pressure will ensure the diagnosis will be much more streamlined than having to involve the use of a stopwatch in the diagnostic evaluation. The advent of safe and effective drugs, e.g. dapoxetine [2] (Johnson & Johnson) and PSD502 [3] (Plethora Solutions), will undoubtedly lead to new diagnostic methodology. In ED this was led by Pfizer; in the case of PE it is unlikely that the pharmaceutical industry will lead the charge. They are more likely to adopt the posture that as drug prescription is largely reliant on physician evaluation (often subjective) and patient choice, that the quantification of IELT is relatively unimportant in the diagnostic algorithm. Further, at least half of all PDEi prescriptions (and an even greater percentage of PDEi use) would be to individuals failing to meet an IIEF-based diagnosis of ED. Overall, it is unlikely that industry will have much more investment in diagnostic tools.

It could be argued that the ISSM definition of PE will be of considerable value to patients with PE due to having brought some degree of structure to clinical trials design and regulatory approval; job done, perhaps. The utility of this definition as a diagnosis of PE or ‘normal’ is much less certain.

Ancillary