Clinical trial management: a profession in crisis?

Clinical trial managers play a vital role in the design and conduct of clinical trials in the UK. There is a current recruitment and retention crisis for this specialist role due to a complex set of factors, most likely to have come to a head due to the COVID-19 pandemic. Academic clinical trial units and departments are struggling to recruit trial managers to vacant positions, and multiple influences are affecting the retention of this highly skilled workforce. Without tackling this issue, we face major challenges in the delivery on the Department of Health and Social Care's Future of UK Clinical Research Delivery implementation plan. This article, led by a leading network of and for UK Trial Managers, presents some of the issues and ways in which national stakeholders may be able to address this.

The EVerT2 (Effective Verruca Treatments 2) trial: a randomized controlled trial of needling vs. nonsurgical debridement for the treatment of plantar verrucae.

BACKGROUND: Verrucae are a common foot skin pathology, which can in some cases persist for many years. Plantar verrucae can be unsightly and painful. There are a range of treatment options including needling. OBJECTIVES: The EVerT2 (Effective Verruca Treatments 2) trial aimed to evaluate the clinical and cost-effectiveness of the needling procedure for the treatment of plantar verrucae, relative to callus debridement. METHODS: This single-centre randomized controlled trial recruited 60 participants (aged ≥ 18 years with a plantar verruca). Participants were randomized 1 : 1 to the intervention group (needling) or the control group (debridement of the overlying callus). The primary outcome was clearance of the index verruca at 12 weeks after randomization. Secondary outcomes included recurrence of the verruca, clearance of all verrucae, number of verrucae, size of the index verruca, pain and participant satisfaction at 12 and 24 weeks. A cost-effectiveness analysis was carried out from the National Health Service perspective over 12 weeks. RESULTS: Sixty eligible patients were randomized (needling group n = 29, 48%; debridement group n = 31, 52%) and 53 were included in the primary analysis (needling n = 28, 97%; debridement n = 25, 81%). Clearance of the index verruca occurred in eight (15%) participants (needling n = 4, 14%; debridement n = 4, 16%; P = 0·86). The needling intervention costs were on average £14·33 (95% confidence interval 5·32-23·35) more per patient than for debridement. CONCLUSIONS: There is no evidence that the needling technique is more clinically or cost-effective than callus debridement. The results show a significant improvement in pain outcomes after needling compared with the debridement treatment alone.

No difference found in time to publication by statistical significance of trial results: a methodological review.

OBJECTIVE: Time-lag from study completion to publication is a potential source of publication bias in randomised controlled trials. This study sought to update the evidence base by identifying the effect of the statistical significance of research findings on time to publication of trial results. DESIGN: Literature searches were carried out in four general medical journals from June 2013 to June 2014 inclusive (BMJ, JAMA, the Lancet and the New England Journal of Medicine). SETTING: Methodological review of four general medical journals. PARTICIPANTS: Original research articles presenting the primary analyses from phase 2, 3 and 4 parallel-group randomised controlled trials were included. MAIN OUTCOME MEASURES: Time from trial completion to publication. RESULTS: The median time from trial completion to publication was 431 days (n = 208, interquartile range 278-618). A multivariable adjusted Cox model found no statistically significant difference in time to publication for trials reporting positive or negative results (hazard ratio: 0.86, 95% CI 0.64 to 1.16, p = 0.32). CONCLUSION: In contrast to previous studies, this review did not demonstrate the presence of time-lag bias in time to publication. This may be a result of these articles being published in four high-impact general medical journals that may be more inclined to publish rapidly, whatever the findings. Further research is needed to explore the presence of time-lag bias in lower quality studies and lower impact journals.

EVerT: cryotherapy versus salicylic acid for the treatment of verrucae--a randomised controlled trial.

OBJECTIVE: To compare the clinical effectiveness and cost-effectiveness of cryotherapy using liquid nitrogen versus patient daily self-treatment with 50% salicylic acid for the treatment of verrucae (plantar warts). DESIGN: A multicentre, pragmatic, open, two-armed randomised controlled trial with an economic evaluation. Randomisation was simple, with the allocation sequence generated by a computer in a 1 : 1 ratio. SETTING: Podiatry clinics, university podiatry schools and primary care in England, Scotland and Ireland. PARTICIPANTS: Patients were eligible if they presented with a verruca which, in the opinion of the health-care professional, was suitable for treatment with both salicylic acid and cryotherapy, and were aged 12 years and over. INTERVENTIONS: Cryotherapy using liquid nitrogen delivered by a health-care professional compared with daily patient self-treatment with 50% salicylic acid (Verrugon, William Ransom & Son Plc, Hitchin, UK) for a maximum of 8 weeks. MAIN OUTCOME MEASURES: The primary outcome was complete clearance of all verrucae at 12 weeks. Secondary outcomes were complete clearance of all verrucae at 12 weeks, controlling for age, whether or not the verrucae had been previously treated and type of verrucae, with a second model to explore the effect of patient preferences, time to clearance of verrucae, clearance of verrucae at 6 months, number of verrucae at 12 weeks and patient satisfaction with the treatment. RESULTS: In total, 240 eligible patients were recruited, with 117 patients allocated to the cryotherapy group and 123 to the salicylic acid group. There was no evidence of a difference in clearance rates between the treatment groups in the primary outcome [17/119 (14.3%) in the salicylic acid group vs 15/110 (13.6%) in the cryotherapy group; p = 0.89]. The results of the study did not change when controlled for age, whether or not the verrucae had been previously treated and type of verrucae, or when patient preferences were explored. There was no evidence of a difference in time to clearance of verrucae between the two groups [hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.51 to 1.25; p = 0.33] or in the clearance of verrucae at 6 months (33.7% cryotherapy vs 30.5% salicylic acid). There was no evidence of a difference in the number of verrucae at 12 weeks between the two groups (incidence rate ratio 1.08, 95% CI 0.81 to 1.43; p = 0.62). Nineteen participants reported 28 adverse events, 14 in each group, with two treatment-related non-serious adverse events in the cryotherapy group. Cryotherapy was also associated with higher mean costs per additional healed patient (£101.17, 95% bias-corrected and accelerated CI £85.09 to £117.26). The probability of cryotherapy being cost-effective is 40% for a range of willingness-to-pay thresholds of £15,000-30,000 per patient healed. CONCLUSIONS: There is no evidence for a difference in terms of clearance of verrucae between cryotherapy and salicylic acid (at both 12 weeks and 6 months), number of verrucae at 12 weeks and time to clearance of verrucae. Cryotherapy was associated with higher mean costs per additional healed patient compared with salicylic acid. TRIAL REGISTRATION: Current Controlled Trials ISRCTN18994246. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 15, No. 32. See the HTA programme website for further project information.

Can vitamin D supplementation prevent winter-time blues? A randomised trial among older women.

BACKGROUND: Seasonal Affective Disorder (SAD) is a sub-type of depression that only occurs during the winter months. A reduction in vitamin D may be linked to SAD. Since vitamin D deficiency has been reported to be common in older people, vitamin D supplementation may be expected to reduce seasonal mood disturbance in this group. OBJECTIVE: To assess the effect of vitamin D supplementation on the mental health of older women. SETTING: Primary care in three areas of the UK (Herts, Newcastle, York). SUBJECTS: Women aged 70 years or more recruited to the trial in the months May-October. INTERVENTION: Eligible women were randomised to receive calcium and vitamin D supplementation or no supplementation. OUTCOME MEASURE: At baseline and the six monthly assessment the mental component score (MCS), calculated from the SF-12 questionnaire was used to assess participants' subjective psychological well-being. RESULTS: A total of 2117 women recruited to the trial had their baseline measures taken between the months of May-October (1205 woman in the control group and 912 women in the intervention group). Of these women, 1621 had a MCS score at baseline and six months. Comparison of the six month mean MCS scores, adjusting for baseline MCS score and age, showed there was no significant difference between the two scores (p = 0.262). CONCLUSIONS: Supplementing elderly women with 800 IU of vitamin D daily did not lead to an improvement in mental health scores.

Risk factors for fracture in a UK population: a prospective cohort study.

BACKGROUND: Common clinical risk factors for fracture in older women have been identified. To date, most of these risk factors have not been confirmed in a UK population. AIM: To confirm the important risk factors for fracture in older women. DESIGN: Comprehensive cohort study (CCS) with a nested randomized controlled trial. METHODS: The CCS included 4292 women aged >70 years. We assessed potential risk factors for fracture, and followed-up participants for 24 months for incidence of non-vertebral fractures. RESULTS: Odds ratios (ORs) for predicting any non-vertebral fracture were: previous fracture, 2.67 (95%CI 2.10-3.40); a fall in the last 12 months, 2.06 (95%CI 1.63-2.59); and age (per year increase), 1.03 (95%CI 1.01-1.05). ORs for predicting hip fracture were: previous fracture, 2.31 (95%CI 1.31-4.08); low body weight (<58 kg), 2.20 (95%CI 1.28-3.77); maternal history of hip fracture, 1.68 (95%CI 0.85-3.31); a fall in the last 12 months, 2.92 (95%CI 1.70-5.01); and age (per year increase), 1.09 (95%CI 1.04-1.13). ORs for predicting wrist fracture were: previous fracture, 2.29 (95%CI 1.56-3.34); and a fall in the last 12 months, 1.60 (95%CI 1.10-2.31). Being a current smoker was not associated with an increase in risk, and was consistent across all fracture types. DISCUSSION: Older women with the clinical risk factors identified in this study should be investigated for osteoporosis or offered preventive treatment.

Angry back syndrome is often due to marginal irritants: a study of 17 cases seen over 4 years.

17 patients with angry back syndrome were identified over a 4-year period (1994-97). 10 such patients were classified as multiple reactors and 7 as exacerbations of atopic eczema. The 10 multiple reactors reacted most commonly to medicaments, rubber chemicals, fragrances, methylchloroisothiazolinone/methylisothiazolinone, colophonium and nickel. A final diagnosis of relevant allergic contact dermatitis was made in 8 of the 10 patients with multiple reactions. Relevant contact allergens were rubber chemicals, plants, metals and preservatives, all of which can be marginal irritants. None of the reactions in the patients with exacerbation of dermatitis were thought to be relevant or helpful in the further management of the patient. Reactions in the angry back syndrome appear to be due most commonly to marginal irritants. In multiple reactors, marginal irritants were also the most common allergens finally identified.

Squamous cell carcinoma arising in Hailey-Hailey disease of the vulva.

A 61-year-old woman, who was known to have Hailey-Hailey disease, presented with increasing vulval soreness. Biopsy showed vulval intraepithelial neoplasia (VIN) 3 and subsequent histology from a vulvectomy specimen showed extensive VIN with early invasive squamous cell carcinoma. This may be another example of chronic inflammation of the vulval area leading to the development of squamous cell carcinoma. However, in this case, chronic human papillomavirus may also have played a part, leading to VIN and reactivation of the Hailey-Hailey disease. We can find no previous reports of squamous cell carcinoma developing in the setting of Hailey-Hailey disease.

Oleogranulomatous response in lymph nodes associated with emollient use in Netherton's syndrome.

Paraffin-based emollients are widely used in dermatological practice and are not usually absorbed through the skin. We report a case where transcutaneous transfer did occur in the context of damaged skin in Netherton's syndrome, resulting in a reversible lymphadenopathy.