Scott Haughie

A placebo-controlled study investigating the efficacy and safety of the phosphodiesterase type 5 inhibitor UK-369,003 for the treatment of men with lower urinary tract symptoms associated with clinical benign prostatic hyperplasia

Study Type – Therapy (RCT)
Level of Evidence 1b

A tool to assess the quality of a meta-analysis

BACKGROUND Because meta-analyses are increasingly prevalent and cited in the medical literature, it is important that tools are available to assess their methodological quality. When performing an empirical study of the quality of published meta-analyses, we found that existing tools did not place a strong emphasis on statistical and interpretational issues. METHODS We developed a quality-assessment tool using existing materials and expert judgment as a starting point, followed by multiple iterations of input from our working group, piloting, and discussion. After having used the tool for our empirical study, agreement for four key items in the tool was measured using weighted kappa coefficients. RESULTS Our tool contained 43 items divided into four key areas (data sources, analysis of individual studies, meta-analysis methods, and interpretation), and each area ended with a summary question. We also produced guidance for completing the tool. Agreement between raters was fair to moderate. CONCLUSIONS The tool should usefully inform subsequent initiatives to develop quality-assessment tools for meta-analysis. We advocate use of consensus between independent raters when assessing statistical appropriateness and adequacy of interpretation in meta-analyses.

A placebo-controlled exploratory study investigating the efficacy and safety of the phosphodiesterase type 5 inhibitor UK-369,003 for the treatment of men with storage lower urinary tract symptoms associated with a clinical diagnosis of overactive bladder

Study Type – Therapy (RCT)
Level of Evidence 1b

Discovery of a Selective Small-Molecule Melanocortin-4 Receptor Agonist with Efficacy in a Pilot Study of Sexual Dysfunction in Humans

The relevance of the melanocortin system to sexual activity is well established, and nonselective peptide agonists of the melanocortin receptors have shown evidence of efficacy in human sexual dysfunction. The role of the MC4 receptor subtype has received particular scrutiny, but the sufficiency of its selective activation in potentiating sexual response has remained uncertain owing to conflicting data from studies in preclinical species. We describe here the discovery of a novel series of small-molecule MC4 receptor agonists derived from library hit 2. The addition of methyl substituents at C3 and C5 of the 4-phenylpiperidin-4-ol ring was found to be markedly potency-enhancing, enabling the combination of low nanomolar potencies with full rule-of-five compliance. In general, the series shows only micromolar activity at other melanocortin receptors. Our preferred compound 40a provided significant systemic exposure in humans on both sublingual and oral administration and was safe and well tolerated up to the maximum tested dose. In a pilot clinical study of male erectile dysfunction, the highest dose of 40a tested (200 mg) provided a similar level of efficacy to sildenafil.

Influence of Sildenafil on Genital Engorgement in Women with Female Sexual Arousal Disorder

INTRODUCTION We previously described dynamic, noncontrast magnetic resonance imaging (MRI) of the female genitalia as a reproducible, nonintrusive, objective means of quantifying sexual arousal response in women without sexual difficulties. These studies showed an increase in clitoral engorgement ranging from 50 to 300% in healthy women during sexual arousal. AIM This study sought to evaluate the genital arousal response in women with female sexual arousal disorder (FSAD) after administration of sildenafil and placebo. We performed a multicenter, double-blind, placebo-controlled, cross-over study to assess the clitoral engorgement response using dynamic MRI in women with FSAD after administering sildenafil and placebo followed by audiovisual sexual stimulation (AVSS). METHODS Nineteen premenopausal women with FSAD underwent two MRI sessions. Subjects were randomized to receive either (i) sildenafil 100 mg during the first session followed by placebo during the second session, or (ii) placebo followed by sildenafil. During each session, baseline MR images were obtained while subjects viewed a neutral video. Subjects then ingested sildenafil or placebo. After 30 minutes, a series of MRIs were obtained at 3-minute intervals for 10 time points while subjects viewed AVSS. MAIN OUTCOME MEASURES A positive sexual arousal response was achieved if clitoral volume increased ≥50% from baseline. RESULTS Thirteen of 19 (68%) subjects achieved a ≥50% increase in clitoral engorgement from baseline when administered sildenafil or placebo 30 minutes after dose administration. At 60 minutes after administration, 17/19 (89%) subjects receiving sildenafil and 16/19 (84%) subjects receiving placebo had responded (P value 0.3173). CONCLUSIONS Sildenafil did not augment the genital response in women with FSAD. Secondarily, a majority of women in this study did not have impaired clitoral engorgement as measured by MRI, suggesting that FSAD is not predominantly a disorder of genital engorgement.

Methodological quality of meta-analyses : matched-pairs comparison over time and between industry sponsored and academic-sponsored reports

CONTEXT Meta-analyses are regularly used to inform healthcare decisions. Concerns have been expressed about the quality of meta-analyses and, in particular, about those supported by the pharmaceutical industry. OBJECTIVE The objective of this study is to compare the quality of pharmaceutical-industry-supported meta-analyses with academic meta-analyses and of meta-analyses published before and after companies started to disclose their data. DATA SOURCES We identified industry-supported meta-analyses by searching the Scopus bibliographic database, using author affiliations. We matched each industry-supported meta-analysis with an academic meta-analysis using high-level MeSH terms in PubMed. STUDY SELECTION We included meta-analyses of randomized trials assessing the efficacy or safety of any pharmaceutical intervention in humans, published in 2002-2004 or 2008-2009. Cochrane reviews were excluded. Two individuals independently selected papers, with discrepancies resolved by two further individuals. ASSESSMENT We developed and piloted a quality-assessment tool, consisting of 43 questions in four domains, with a key summary question covering each domain. Two individuals independently assessed each meta-analysis. RESULTS We examined 126 meta-analysis publications in 63 matched pairs. The average quality was low, with fewer than 50% adequate in three of the four domains. Industry-supported meta-analyses less often demonstrated adequate methods for locating studies and assessing their quality (odds ratio 0.44, 95% confidence interval 0.21 to 0.92), for analysing the included studies (0.52, 0.25 to 1.06), for undertaking meta-analyses (0.82, 0.40 to 1.68) and in reaching sound conclusions (0.62, 0.30 to 1.28). Quality generally improved over time, particularly for some aspects of industry reports. CONCLUSIONS Academic meta-analysis papers are generally of higher quality than industry-supported ones. This is largely due to less detailed reporting in industry-supported meta-analyses and a tendency for them to take the included studies at face value, probably arising from the implicit assumption that these studies already have high methodological standards to meet licensing requirements. The improved quality over time does not appear to be due to the use of data disclosed by industry. The main limitations of this study are the small sample of papers and the subjective nature of some of the assessment processes.

Re: Randomized Controlled Trial to Evaluate Transdermal Testosterone in Female Cancer Survivors With Decreased Libido: North Central Cancer Treatment Group Protocol N02C3

Barton et al. ( 1 ) presented the results of the analyses of various endpoints from a twoperiod crossover trial to compare active drug and placebo for the treatment of loss of libido in female cancer survivors. The authors stated that they had used a methodology for their analyses that “encompasses the state of the science for crossover studies.” However, the results given in their table 2, and the subsequent conclusions made, are clearly not based on the correct crossover trial analyses. The correct methodology is described in Chapter 2 of the book by Jones and Kenward ( 2 ). Curiously, it is stated by Barton et al. that they have followed such methodology, referring to it in their article as the “sums and differences” analysis. However, what the authors have reported in their table 2 are P values for the comparison of drug and placebo in each period. Such comparisons are based on the variability between subjects and are therefore not correct for the analysis of a crossover trial. The correct analysis is based on the within-subject differences between the second and fi rst period measurements [see Section 2.3 of ( 2 )]. The authors also advocate using the test for a carryover difference as a preliminary test for deciding if the test for drug vs placebo should be based either 1) on only the data from the fi rst period or 2) on the data from both periods. This procedure is seriously fl awed, as pointed out by Freeman ( 3 ) and further illustrated in Section 2.7 of ( 2 ).