Sildenafil (Viagra) for male erectile dysfunction: a meta-analysis of clinical trial reports (2024)

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Supplementary Materials

Abstract

Background

Meta-analyses that include otherwise unpublished randomised trials are uncommon [1], but are welcome, and can inform in circ*mstances where information is contradictory. The example of tramadol in acute pain, where information on 3,500 patients was made available, explained the results of two studies, one showing that tramadol was a highly efficacious analgesic [2], the other showing it to be no different from placebo [3]. The truth was somewhere between. Despite the fact that tramadol had been in common use in some European countries for many years, fulfilling regulatory requirements for the United States required studies to be conducted to contemporary requirements, and meta-analysis brought useful results to light.

Meta-analysis of randomised studies before a new technology has become commercially available is even more rare, though there is at least two examples [4,5]. Meta-analyses are usually performed some years after first commercial availability because the publication of randomised trials performed for efficacy and/or safety reasons takes time. The importance of meta-analysis in drug development and regulatory procedures is increasingly recognised [5,6].

The results of meta-analysis are undoubtedly important, both in the regulatory process and for evaluation of rare but serious adverse events. For COX-2 inhibitors meta-analysis was being planned before the randomised trials in order to examine the relationship between treatments and rare events [5,6].

The point of greatest change, though, is in the period immediately after commercial introduction. Media interest can raise patient expectations at a time where healthcare professionals and organisations have least knowledge and experience, and when few have had the opportunity to consider the full implications of the new technology on budgets and services. For sildenafil, for instance, 85% of first time prescriptions occurred in the first 12 weeks of availability in one New England healthcare provider [7]. It is at this point, the point of marketing approval, when there is the greatest need for the best information. At best only a small number of trials may have been published, and though they can be large, and usually are powered to detect a difference from placebo or common current practice, they are unlikely to be able to measure accurately the size of the benefit.

We sought to assess whether clinical trial reports presented for marketing approval would provide the basis for a systematic review at the time of launch if they were publicly available. We did this with reference to the erectile dysfunction treatment sildenafil (Viagra), using clinical trial reports made available by Pfizer Ltd.

Methods

No search strategy was required because this review was of material made available by Pfizer UK Ltd in the form of clinical trial reports used in a marketing authorisation application for sildenafil (Viagra) in September 1997. QUORUM guidelines were otherwise followed [7]. The prior intention was to use studies that were relevant to the use of sildenafil in clinical practice. This required the setting to be the home, not the clinic, use of sildenafil as required, rather than fixed dosing schedules (such as daily tablets), and studies of a minimum duration, which we set arbitrarily as four weeks.

Excluded were studies with laboratory measures of penile tumescence or rigidity with single doses of sildenafil, studies that only investigated erectile function in a clinic setting, studies that used fixed daily dosing rather than as required, and studies that were shorter than four weeks. Included were randomised trials that investigated sildenafil, with efficacy or safety data, were longer than four weeks, conducted in the home setting, and with doses in the licensed range of 25 mg to 100 mg as required, although lower and higher doses would be analysed if there were sufficient information. Clinical trials in men with erectile dysfunction caused specifically by single causes like spinal cord trauma or diabetes were not included because, taken with the other data, they would constitute clinical heterogeneity.

Each report was scored for quality using a three item, 1–5 score, quality scale [8]. Points were awarded to studies according to whether they were randomised and double blind and mentioned withdrawals or drop-outs from the study. An additional point was awarded if the method of randomisation or double blinding was described and was appropriate.

From each trial we extracted the number of patients treated per group, dosing regimen, study design, and the number of patients with efficacy and/or safety outcomes. The denominator was the number of patients randomised so that results were on an intention-to-treat basis. This analysis includes all randomised patients regardless of the completion of diaries, protocol concordance or missing data. Patients with missing or illegible diary data were assumed to have 0% intercourse success rate. In addition, this analysis included sexual intercourse attempts that were unsuccessful for reasons not attributable to sildenafil i.e. factors other than the erection being insufficiently hard or long-lasting. RAM extracted the data into tables, and these were then read and checked by other authors.

For the review, a prior definition of efficacy was a man with a consistent three-part outcome, consisting of an erection, sufficiently rigid for penetration, and followed by successful intercourse. Other efficacy outcomes of interest were the number of men with the highest two responses on the International Index of Erectile Function (IIEF) questions 3 and 4, and global evaluations of treatment efficacy by patients [9]. The number of grade 3 or 4 erections (at least hard enough for penetration) and successful erections were also noted.

Adverse events were also sought. These were the number of men with any treatment-related adverse event, the total number of men discontinuing, those discontinuing through lack of efficacy or through adverse events, adverse events rated severe or serious, and information on particular adverse events.

Results

Twenty-seven clinical trial reports were made available, all prepared for a marketing authorisation application, and dated September 1997. Some of these were single dose use in laboratory setting with penile plethysmography as an outcome. Others were open extensions of randomised studies. These were not useful, and 17 were excluded; details of excluded studies and reasons for exclusions are given in Additional File 1. There were no details of any ongoing studies.

Ten studies could be included (study report numbers 101, 102, 103, 106, 355, 356, 359, 361, 363, 364) with 1846 men given sildenafil (25 to 100 mg) and 1131 given placebo. An additional 277 men were given sildenafil at 5 mg or 200 mg. Details of trial design for the included studies is given in Additional File 2. Nine were parallel group and one had a crossover design, with fixed doses of sildenafil, or dose-optimised sildenafil, or both, and all had a placebo comparator group. Study duration was a minimum of six weeks and a maximum of six months.

Results Of meta-analysis

Discussion

This review demonstrated that considerable amounts of useful information are available in clinical trial reports submitted for marketing authorisation (licensing). That information adequately describes research methods used, though could be improved, perhaps using the updated CONSORT criteria [17]. If these guidelines are becoming necessary for publication of randomised trials in our major medical journals, then they should be minimum criteria for clinical trials reports required by licensing authorities. We did not check the reports against each CONSORT criterion because the reports were from 1997 soon after the publication of the original CONSORT statement [17].

Despite scores of 3 or 4 out of five on a commonly-used quality score, and acknowledging that scores like this are not associated with bias [18,19], the areas where the clinical trials reports were weak were important ones. Only two reports stated how the randomisation sequence was generated. No report adequately described allocation concealment, though several mentioned sealed envelopes. No report described the implementation of the allocation sequence. Only two reports described how double blinding was achieved.

In other areas, reporting was good. Participants, and inclusion and exclusion criteria were explicit, as was a description of the intervention. Patient flow (though without diagrams) was thoroughly described, together with reasons for withdrawal. Baseline information on participants, numbers analysed and methods used were all well described, both for efficacy and adverse events. One criticism, outside CONSORT, was the use of mean scores for results of IIEF questions. Mean scores are of little value, especially when there may not be a normal distribution when they can be misleading [10]. Better would be the number or proportion of men achieving good or excellent outcomes.

Clinical trial reports were a good source of information, and with minor changes would become an excellent source of information for meta-analysis. For sildenafil in erectile dysfunction these reports allowed interesting conclusions to be drawn from a hom*ogeneous population of men with similar aetiologies, but excluding those with erectile dysfunction following spinal cord trauma, with diabetes, or following treatment for prostate cancer. Although two small studies on spinal cord trauma and one on diabetes were available in the full review, much more information on men with erectile dysfunction of particular aetiology has become available since 1997 [19], [19], [20], [21], [22], [23].

Efficacy was available in a number of formats in addition to mean responses to IIEF scores 3 and 4. The number of men in whom sildenafil was successful (erections hard enough for penetration, and resulting in intercourse) more than 60% of the time, and more than 40% of the time was available, and chosen by us for evaluation. Cut points every 20% from 0% to 100% were also available. The number of men responding positively to the global question on improved erections was also available. Clearly there is a gradation here from outcomes that are less easy to achieve to those that are easier to fulfil. A greater proportion of men achieved the easier than harder outcome for all doses (Figure ​(Figure5).5). Numbers needed to treat and the proportion of patients achieving the outcome could easily be calculated.

Adverse events were also well described, and presented in a number of formats, from the number of men with any treatment related adverse event, through the number with severe or serious adverse events, particular adverse events, and discontinuations. From these it was possible to calculate numbers needed to harm and the proportion of patients for each outcome.

The ability to perform these calculations with information pooled from 10 studies was informative. Firstly, it supported the optimised dosing regimen for sildenafil. Optimised dosing produced efficacy equivalent to the highest fixed dose, and harm equivalent to the lowest fixed dose. Figure ​Figure66 shows the effects on the two broadest efficacy and harm outcomes, global response about improved erections and treatment related adverse effects. Figure ​Figure77 shows the NNTs and NNHs for three efficacy outcomes, three harm outcomes and three discontinuation outcomes. Optimised dosing was better than fixed dosing.

It is also germane to enquire whether results obtained from clinical trial reports of the earliest studies are borne out in later reviews. A review of 20 trials comparing sildenafil with placebo with about 4,000 men included both published and unpublished information, and supplemented by the manufacturer where appropriate, arrived at broadly similar results [24]. Only seven of the references to trials in that review were dated 1997 or before (mostly as abstracts), and would have been available at the time of marketing approval. Though combining all doses of sildenafil from 5 mg to 200 mg and dose escalation together in a comparison with placebo, the result for global efficacy yielded an NNT of 2, the same as is found in this review for all doses higher than 25 mg (Table ​(Table33).

This investigation of the evidential properties of clinical trial reports of sildenafil for treatment of erectile dysfunction indicates that, in this instance, reports could have been used for systematic review at the time of product launch. With little additional effort the clinical trial reports could have fulfilled CONSORT guidelines for the reporting of randomised controlled trials. Making clinical trial reports publicly available at the time of product launch, perhaps through the Internet, would make their introduction evidence-based, as well as allowing healthcare services to plan ahead more effectively. This would benefit commercial organisations by maximising the uptake of effective new technology, and may accelerate discontinuation of less effective, or less safe, older technology.

Conclusions

Clinical trial reports presented for marketing approval did provide the basis for a systematic review at the time of launch for sildenafil for the treatment of male erectile dysfunction. To our knowledge these documents were not publicly available at the time. Were clinical trials reports used for marketing approval publicly available, then review and meta-analysis would allow an early appreciation of benefits or pitfalls§for patients and healthcare systems.

Competing interests

RAM has received lecture fees on one occasion related to erectile dysfunction. All authors have worked with commercial, government and charities in relation to healthcare, but not in regard to erectile dysfunction.

Authors' contributions

RAM read each report, abstracted information and analysis, and performed quality scoring. JE read each report, checked abstracted information and analysis, and performed quality score. HJM checked quality scores. All authors contributed equally to the preparation and writing of the manuscript.

Pre-publication history

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1471-2490/2/6/prepub

Supplementary Material

Acknowledgements

References