Andrew Grey

The integrity of evidence synthesis is threatened by problematic randomised controlled trials, where there are serious concerns about the trustworthiness of the data or findings. Such concerns could be due to research misconduct, including fraud, or due to honest critical errors. If these trials are not detected, they may be inadvertently included in systematic reviews and guidelines, potentially distorting their results. To resolve this problem, the INSPECT-SR (Investigating Problematic Clinical Trials in Systematic Reviews) tool has been developed to assess the trustworthiness of randomised controlled trials. This tool will help researchers to identify and exclude problematic trials from systematic reviews. This article describes the development of INSPECT-SR and presents the tool and an associated guidance document.

Early notification of journal readers of the existence of publication integrity concerns by an editorial expression of concern (EoC) can mitigate the adverse effects of unreliable research. We extracted EoCs and retraction notices from the Retraction Watch database up until the end of 2024. We assessed temporal trends in publication of each notice, the proportion of retracted papers with an associated EoC, and the timing of EoCs according to publication date and retraction status. We examined the ratio of EoCs to retractions among authors, including those with multiple retractions, and among both journals and publishers. EoCs were rarely published during the 14y assessment period. Only 3.3% of retracted papers had a preceding EoC. For 56% of publications with an EoC, the EoC was the latest notice. 92% of authors had an EoC:retraction ratio < 1. Only 35% of authors with > 5 retractions had an EoC, and 99% had an EoC:retraction ratio < 1. Publication of an EoC was more common in journals which had published > 5 retractions than in those which had published < 5. EoCs are rarely employed during the assessment of publication integrity concerns. Journal readers are disadvantaged by delayed notification of potentially unreliable research.

Objective: Vitamin D testing uses considerable resources and has increased recently. We investigated repeating testing in Auckland, New Zealand. Design, Measurement and Patients: We analysed repeated 25‐hydroxyvitamin D (25OHD) tests in three databases from the Auckland region from 2005 to 2024 (362,618 tests). We assessed annual numbers, time between tests, characteristics associated with repeat tests, and relationships between requestors and repeated tests. Results: Twenty‐four percent of individuals had ≥ 2 25OHD tests. 34% of all 25OHD tests were repeats. A disproportionately high number of repeat tests were done in a small number of individuals: 57% had one repeated test (i.e., two tests total) but 5.3% had ≥ 6 and 1.4% had ≥ 11 repeated tests. Fifty eight percentage of repeat tests were done within 1 y and 77% within 2 y. 85% of people with repeated tests had a first 25OHD > 25 nmol/L, but in only 9.8% a repeated 25OHD was ≤ 25 nmol/L. Most repeat tests (77%) when the first 25OHD was > 75 nmol/L were > 75 nmol/L A small number of high‐volume requestors ordered most tests: 3/7637 ordered > 5000 tests, collectively 7% (21,092) of the total, and 98 ordered > 500 tests (collectively 44%). The most frequent requestors were primary care doctors and bariatric surgeons. Simple restrictions based on the result and time since previous 25OHD could reduce repeated tests by > 60%–90% with only 4%–5% of 'avoided' tests ≤ 25 nmol/L. Conclusion: Repeated vitamin D testing is common, and most results are not low. Restricting test availability and targeting those at risk of clinical complications of vitamin D deficiency are likely to reduce unnecessary tests.

Zoledronate prevented fractures in 4 large trials in cohorts that varied from low to high risk of fracture. Cost-effectiveness analyses are important tools used in funding and regulatory decisions about pharmaceutical agents, and zoledronate generally has appeared to be cost-effective. We used a simple approach to compare zoledronate costs with the savings from fractures prevented to complement previous cost-effectiveness analyses. Eighteen month costs of major osteoporotic fractures were obtained from published data from 7 US sites in the International Costs and Utilities Related to Osteoporotic Fractures Study (ICUROS) study, costs of zoledronate medication from Medicare, and infusion costs estimated empirically. We applied these costs to data on major osteoporotic fracture from the 4 trials. We repeated these analyses using 12-mo costs from 11 international ICUROS sites. In the trials with high-risk and intermediate-high risk cohorts, the cost-savings from major osteoporotic fractures prevented were approximately US $500 000/1000 patients/3 yr. In the low-intermediate-risk trial, they were $660 000/1000/6 yr, and in the low-risk trial, $240 000/1000/10 yr. When the international fracture cost data were used, these savings approximately doubled. In all 4 trials, the total costs of zoledronate were substantially less than the savings from fractures prevented, with annual savings ranging from $11 to $88/patient/yr in low-risk to high-risk patients. The cost-neutral zoledronate cost (maximum infusion cost plus medication cost) ranged from $160 to $175 using the US fracture cost data, and was about $350 using international cost data. In summary, in 4 trials with cohorts at various risk of fracture ranging from low to high risk, zoledronate produced substantial net savings because the costs of fractures prevented out-weighed total zoledronate costs.

Background: Journals may respond to integrity concerns by publishing an editorial response (editorial notice, expression of concern (EoC) or retraction). We investigated whether the type of editorial response affected citation rates. Methods: We obtained citations for 172 randomised controlled trials (RCTs) with integrity concerns (41 had editorial notices, 38 EoCs and 23 retractions) and control RCTs from the same journal and year. Monthly citation rates up to 60 months before and after editorial responses were compared by editorial response type, and to citation decline in control RCTs. Results: 172 RCTs had 10,603 citations from 6,376 articles. 3,330 control trials were identified for 151/172 RCTs (15,948 citations, 87,811 articles). For both groups, citations increased steadily, peaking 45-65 months post-publication. There were no statistically significant differences in citation decline post-editorial response for trials receiving a retraction, EoC, or notice. Citations were lower in controls than index trials, so analyses were restricted to 1598 highly cited (>25) controls. The rate of decline for highly cited control trials was not statistically significantly different from the post-editorial response rate for index groups. Conclusion: Citation rate decline after editorial responses did not differ by type of editorial response nor from the natural decline in control trials. Highlights: Journals may respond to integrity concerns by issuing an editorial notice. The effect of expressions of concern or other editorial notices on citation patterns is unclear. Editorial notices did not accelerate citation decline compared with control trials. The type of notice was not associated with differences in citation decline. Late editorial notices appear ineffective in preventing continued citation.

A reliable biomedical literature is critical to scientific advances and patient care. When concerns about the integrity of a publication are raised, it is

Context: We recently reported that zoledronate (zol) given once at baseline or twice (every 5 years) reduced fracture risk over 10 years. Objective: We assessed whether the effects of zol differ over time or across important baseline variables, and how they relate to changes in bone mineral density (BMD) over time. Methods: A 10-year, prospective, randomized, double-blind, placebo-controlled trial, was conducted at a clinical research center from 2012 to 2023. Participants included 1054 postmenopausal women, aged 50 to 60 years, with BMD T-score at the lumbar spine, femoral neck, or total hip between 0 and −2.5. Intervention included either 5-yearly 5-mg zol (zol-zol), 5-mg zol infusion at baseline and placebo at 5 years (zol-placebo), or 5-yearly placebo (placebo-placebo). Main outcome measures included morphometric vertebral fractures, major osteoporotic, and any fractures. Results: Morphometric vertebral fractures were not reduced in the years 0 to 5 following zol but were reduced in years 5 to 10 by 58% (95% CI, 21%-77%) (zol-zol) and 57% (21%-77%) (zol-placebo). For any fracture and major osteoporotic fracture, similar temporal patterns were observed. There were no interactions between treatment effect and baseline variables (including age, body mass index, BMD, falls or fracture history, and estimated fracture risk) or between treatment effect and changes in BMD with zol. Conclusion: Fracture reductions with single-dose or 5-yearly zol appear greater during years 5 to 10 than years 0 to 5. The risk reductions are broadly consistent across this cohort and independent of baseline or change in BMD. This suggests that routine BMD monitoring may not be necessary for low-risk women considering the option of less frequent zol for long-term fracture risk reduction.