National census of availability of neonatal intensive care. British Association for Perinatal Medicine

ObjectiveTo determine whether availability of neonatal intensive care cots is a problem in any or all parts of the United Kingdom.DesignThree month census from 1 April to 30 June 1999 comprising simple data sheets on transfers out of tertiary units.SettingThe 37 largest high risk perinatal centres in the United Kingdom.ParticipantsOne obstetric specialist and one neonatal specialist in each centre.ResultsAll units provided data. The number of intensive care cots in each unit was between five and 16. During the three months 309 transfers occurred (equivalent to 1236 per year), of which 264 were in utero and 45 postnatal. Sixty five in utero transfers involved multiple births, hence the census related to 382 babies (1528 per year). There was considerable regional variation. The reason for transfer in most cases was “lack of neonatal beds”.ConclusionsCurrently most major perinatal centres in the United Kingdom are regularly unable to meet in-house demand; this has implications for the service as a whole. The NHS has set no standards to help health authorities and primary care groups develop services relating to this specialty; such a step may well be an appropriate lever for change.     

Bone Sarcoma: Treatment by Irradiation,Amputation, or a Combination of the Two

A retrospective survey of all cases of osteosarcoma of the femur and tibia treated at the major centres in the United Kingdom during 1952-9 was carried out in an attempt to assess the respective value of treatment by surgery and radiotherapy and the feasibility of a larger prospective study. Of the 192 patients available for the comparison, those treated by radiotherapy alone did least well. A combination of the two treatments—radiotherapy followed by amputation—produced better results, in terms of survival, than amputation alone; however, the comparatively small numbers involved and the inadequacy of information about the factors dictating the choice of treatment make firm conclusions impossible. A controlled clinical trial on a larger scale might provide answers to the outstanding questions.     

Informing participants of allocation to placebo at trial closure: postal survey

ObjectivesTo assess whether and how investigators of placebo controlled randomised trials inform participants of their treatment allocation at trial closure and to assess barriers to feedback.DesignPostal survey with a semistructured questionnaire.ParticipantsAll investigators who published a placebo controlled randomised trial in 2000 in five leading medical journals, and a random sample of 120 trials listed in the national research register database.Results45% of investigators informed either all or most participants of their treatment allocation, and 55% did not inform any participant or only informed those who asked. The main reasons for not informing participants were that the investigators never considered this option (40%) or to avoid biasing results at study follow up (24%).ConclusionFurther research is required to examine sensitive ways to communicate treatment information to trial participants.

What is already known on this topic

Information is poor on the nature, extent, and effect of informing participants of placebo controlled randomised trials about their treatment allocation at trial closureLess than 50% of participants receiving placebo are informed about their treatment allocation

What this study adds

No standard procedure is available for informing patients of their treatment arm or of study results at the end of a trialEffective and sensitive ways of communicating treatment allocation to participants are required, as is information on the effects on placebo responders     

Evaluating "payback" on biomedical research from papers cited in clinical guidelines: applied bibliometric study

ObjectivesTo develop a methodology for evaluating the impact of research on health care, and to characterise the papers cited on clinical guidelines.DesignThe bibliographic details of the papers cited in 15 clinical guidelines, developed in and for the United Kingdom, were collated and analysed with applied bibliometric techniques.ResultsThe median age of papers cited in clinical guidelines was eight years; most papers were published by authors living in either the United States (36%) or the United Kingdom (25%)—this is two and a half times more than expected as about 10% of all biomedical outputs are published in the United Kingdom; and clinical guidelines do not cite basic research papers.ConclusionAnalysis of the evidence base of clinical guidelines may be one way of tracking the flow of knowledge from the laboratory to the clinic. Moreover, such analysis provides a useful, clinically relevant method for evaluating research outcomes and different strategies in research and development.     

Nonregistration,discontinuation, and nonpublication of randomized trials: A repeated metaresearch analysis

BackgroundWe previously found that 25% of 1,017 randomized clinical trials (RCTs) approved between 2000 and 2003 were discontinued prematurely, and 44% remained unpublished at a median of 12 years follow-up. We aimed to assess a decade later (1) whether rates of completion and publication have increased; (2) the extent to which nonpublished RCTs can be identified in trial registries; and (3) the association between reporting quality of protocols and premature discontinuation or nonpublication of RCTs.Methods and findingsWe included 326 RCT protocols approved in 2012 by research ethics committees in Switzerland, the United Kingdom, Germany, and Canada in this metaresearch study. Pilot, feasibility, and phase 1 studies were excluded. We extracted trial characteristics from each study protocol and systematically searched for corresponding trial registration (if not reported in the protocol) and full text publications until February 2022. For trial registrations, we searched the (i) World Health Organization: International Clinical Trial Registry Platform (ICTRP); (ii) US National Library of Medicine (ClinicalTrials.gov); (iii) European Union Drug Regulating Authorities Clinical Trials Database (EUCTR); (iv) ISRCTN registry; and (v) Google. For full text publications, we searched PubMed, Google Scholar, and Scopus. We recorded whether RCTs were registered, discontinued (including reason for discontinuation), and published. The reporting quality of RCT protocols was assessed with the 33-item SPIRIT checklist. We used multivariable logistic regression to examine the association between the independent variables protocol reporting quality, planned sample size, type of control (placebo versus other), reporting of any recruitment projection, single-center versus multicenter trials, and industry versus investigator sponsoring, with the 2 dependent variables: (1) publication of RCT results; and (2) trial discontinuation due to poor recruitment.Of the 326 included trials, 19 (6%) were unregistered. Ninety-eight trials (30%) were discontinued prematurely, most often due to poor recruitment (37%; 36/98). One in 5 trials (21%; 70/326) remained unpublished at 10 years follow-up, and 21% of unpublished trials (15/70) were unregistered. Twenty-three of 147 investigator-sponsored trials (16%) reported their results in a trial registry in contrast to 150 of 179 industry-sponsored trials (84%).The median proportion of reported SPIRIT items in included RCT protocols was 69% (interquartile range 61% to 77%). We found no variables associated with trial discontinuation; however, lower reporting quality of trial protocols was associated with nonpublication (odds ratio, 0.71 for each 10% increment in the proportion of SPIRIT items met; 95% confidence interval, 0.55 to 0.92; p = 0.009). Study limitations include that the moderate sample size may have limited the ability of our regression models to identify significant associations.ConclusionsWe have observed that rates of premature trial discontinuation have not changed in the past decade. Nonpublication of RCTs has declined but remains common; 21% of unpublished trials could not be identified in registries. Only 16% of investigator-sponsored trials reported results in a trial registry. Higher reporting quality of RCT protocols was associated with publication of results. Further efforts from all stakeholders are needed to improve efficiency and transparency of clinical research.

Benjamin Speich and colleagues investigate whether rates of trial completion and publication have increased over the past decade, the extent to which non-published trials can be identified in registries, and the association between reporting quality of protocols and premature discontinuation or non-publication of trials.     

Paradigms of expected failure

This study explores the outsourcing and offshoring of clinical trials and how they interconnect with the dynamics of drug development and regulation in the United States. I focus on the activities of United States-based contract research organizations, which make up a specialized global clinical trials industry focusing on the recruitment of human subjects and investigators. Tracking this industry’s activities in eastern Europe and Latin America, two clinical trial market ‘growth regions,’ I address the strategies of evidence-making that inform clinical trial offshoring. I also show how aspects of the clinical trial model—in which failures to predict safety outcomes or a paradigm of expected failure—are being exported along with the offshored trial. The clinical trials industry is a crucial, highly mobile, and profitable arm of the global pharmaceutical industry. Where state agencies furnish limited or no health care, drug developers claim that trial expansion and experiments have become social goods in themselves. But questions remain: How is drug value and research integrity maintained? And how do the results of clinical trials strengthen or undermine the delivery of affordable and effective interventions? As this essay shows, clinical trials are not only hypothesis-testing instruments; they are operative environments redistributing resources and occasioning tense medical and social fields. In highlighting the inefficiencies and uncertainties of global drug development, this study points to problems in the operational model of drug development and in systems of human protection. It also considers new forms of accountability at the nexus of private sector science and public health.     

Influence of data display formats on physician investigators’ decisions to stop clinical trials: prospective trial with repeated measures

ObjectiveTo examine the effect of the method of data display on physician investigators’ decisions to stop hypothetical clinical trials for an unplanned statistical analysis.DesignProspective, mixed model design with variables between subjects and within subjects (repeated measures).SettingComprehensive cancer centre.Participants34 physicians, stratified by academic rank, who were conducting clinical trials.InterventionsParticipants were shown tables, pie charts, bar graphs, and icon displays containing hypothetical data from a clinical trial and were asked to decide whether to continue the trial or stop for an unplanned statistical analysis.ResultsAccuracy of decisions was affected by the type of data display and positive or negative framing of the data. More correct decisions were made with icon displays than with tables, pie charts, and bar graphs (82% v 68%, 56%, and 43%, respectively; P=0.03) and when data were negatively framed rather than positively framed in tables (93% v 47%; P=0.004).ConclusionsClinical investigators’ decisions can be affected by factors unrelated to the actual data. In the design of clinical trials information systems, careful consideration should be given to the method by which data are framed and displayed in order to reduce the impact of these extraneous factors.

Key messages

• In clinical trials formal interim monitoring points, at which statistical tests are conducted, are designated a priori, but investigators also conduct informal interim monitoring, when statistical tests are not used
• This study investigated the effect of the method of displaying results on clinical investigators’ decisions to conduct unplanned analyses of a hypothetical clinical trial
• The method of displaying results significantly influenced the accuracy of decisions, as did the framing of these results (positive or negative)
• The display formats preferred by the clinical investigators did not lead to the most accurate decisions
• Careful consideration should be given to the method of data display in information systems supporting clinical research

     

Equity in clinical trials for HIV-associated cryptococcal meningitis: A systematic review of global representation and inclusion of patients and researchers

BackgroundIt is essential that clinical trial participants are representative of the population under investigation. Using HIV-associated cryptococcal meningitis (CM) as a case study, we conducted a systematic review of clinical trials to determine how inclusive and representative they were both in terms of the affected population and the involvement of local investigators.MethodsWe searched Medline, EMBASE, Cochrane, Africa-Wide, CINAHL Plus, and Web of Science. Data were extracted for 5 domains: study location and design, screening, participants, researchers, and funders. Data were summarised and compared over 3 time periods: pre-antiretroviral therapy (ART) (pre-2000), early ART (2000 to 2009), and established ART (post-2010) using chi-squared and chi-squared for trend. Comparisons were made with global disease burden estimates and a composite reference derived from observational studies.ResultsThirty-nine trials published between 1990 and 2019 were included. Earlier studies were predominantly conducted in high-income countries (HICs) and recent studies in low- and middle-income countries (LMICs). Most recent studies occurred in high CM incidence countries, but some highly affected countries have not hosted trials. The sex and ART status of participants matched those of the general CM population. Patients with reduced consciousness and those suffering a CM relapse were underrepresented. Authorship had poor representation of women (29% of all authors), particularly as first and final authors. Compared to trials conducted in HICs, trials conducted in LMICs were more likely to include female authors (32% versus 20% p = 0.014) but less likely to have authors resident in (75% versus 100%, p < 0.001) or nationals (61% versus 93%, p < 0.001) of the trial location.ConclusionsThere has been a marked shift in CM trials over the course of the HIV epidemic. Trials are primarily performed in locations and populations that reflect the burden of disease, but severe and relapse cases are underrepresented. Most CM trials now take place in LMICs, but the research is primarily funded and led by individuals and institutions from HICs.     

Challenges in implementing model-based phase I designs in a grant-funded clinical trials unit

Background

For a clinical trials unit to run its first model-based, phase I trial, the statistician, chief investigator, and trial manager must all acquire a new set of skills. These trials also require a different approach to funding and data collection.

Challenges and discussion

From the statisticians’ viewpoint, we highlight what is needed to move from running rule-based, early-phase trials to running a model-based phase I study as we experienced it in our trials unit located in the United Kingdom. Our example is CHARIOT, a dose-finding trial using the time-to-event continual reassessment method. It consists of three stages and aims to discover the maximum tolerated dose of the combination of radiotherapy, chemotherapy, and the ataxia telangiectasia mutated Rad3-related inhibitor M6620 (previously known as VX-970) in patients with oesophageal cancer. We present the challenges we faced in designing this trial and how we overcame them as a way of demystifying the conduct of a model-based trial in a grant-funded clinical trials unit.

Conclusions

Although we appreciate that undertaking model-based trials requires additional time and effort, they are feasible to implement and, once suitable tools such as guiding publications and document templates become available, the design and set-up process will be easier and more efficient.

     

Radiotherapy as treatment option in biliary cancer patients: a national survey of AIRO (Italian Association of Radiation Oncology) Gastroenterology Group

BackgroundThe aim is to find out how many radiation oncology centres treat biliary duct carcinoma (BDC), what treatments they offer and whether they would be interested in developing prospective trials.Materials and methodsA questionnaire was posted to all 220 Italian Radiation Oncology Centres. The survey consisted of 31 eligibility questions in a combination of multiple and forced choice formats addressing the following parameters: characteristics of the centre, numbers of BDC patients treated, treatment options, radiotherapy parameters (target definition, schedule, technique, dose constraints) and interest in developing future randomized trials.ResultsNo major differences emerged in BDC management, whatever the site, and whether it was resectable or not. Discrepancies in routine clinical practice were, however, observed with lack of agreement on expansion margins, dose constraints and treatment schedules for the stereotactic technique and palliative treatments.ConclusionsThe present survey attempted to fill the gaps in the role of radiotherapy in patients with BDC. Since lack of prospective randomized studies and disease rarity have mitigated against an evidence-based approach, patients with BDC should be enrolled in prospective studies. The above-mentioned results should also emphasize the need to combine analysis of treatment results from all Italian centres in order to create predictive models.     

Cardiovascular drug trials: how to examine interaction, and why so

Background: In practice the benefit of cardiovascular medicines is less consistent than it is in clinical trials. This is due to multiple uncontrolled factors that co-determine the efficacy of the new treatment. In statistical terms, they interact with the new treatment. Interaction effects are rarely assessed in cardiovascular trials. Objective: To review (1) important factors that may interact with the treatment efficacy, (2) how to examine such factors, and (3) why so. Results: Important factors include (a) possible risk factors such as specific patient characteristics, and concomitant medications, and (b) study-specific aspects such as heterogeneities of investigators, health centres, and individual patients including patient compliance. Such factors can be assessed by comparing subgroups. A common but incorrect approach is the comparison of the significances of difference between treatment modalities in either subgroup. Instead, a direct comparison of effect sizes relative to the standard errors is adequate. As an alternative, regression modelling is adequate and convenient. Results of interaction assessments are post-hoc and, therefore, of an exploratory and unconfirmed nature. So, why should they be performed? In cardiovascular research the effects of patient characteristics and drug-drug interactions on drug efficacies are numerous. It is valuable to account at least post-hoc for such mechanisms. Second, current cardiovascular trials involve heterogeneous health centres, investigators, and patient groups. Accounting for these heterogeneities can be helpful to better predict individual responses in future patients. Conclusion: Cardiovascular trials enrolling patient groups at risk for heterogeneity should include at least a post-hoc assessment for interaction. Correct and incorrect methods for that purpose are described. Interaction assessments are helpful to better predict the efficacy/safety of new cardiovascular medicines in the future treatment of subgroups of patients. (Neth Heart J 2007;15:61-6.)     

Attitudes,Perceptions, and Practices Among Endocrinologists Managing Obesity

ObjectiveObesity has been globally recognized as a critically important disease by professional medical organizations, in addition to the World Health Organization and American Medical Association, but health care systems, medical teams, and the public have been slow to embrace this concept.MethodsThe American Association of Clinical Endocrinology staff drafted a survey, and 2 endocrinologists independently reviewed the survey’s questions and modified the survey instrument. The survey included questions related to practice and patient demographics, awareness about obesity, treatment of obesity, barriers to improving obesity outcomes, digital health, cognitive behavioral therapy, lifestyle medicine, antiobesity medications, weight stigma, and social determinants of health. The survey was emailed to 493 endocrinologists, with 305 (62%) completing the study.ResultsOf the responders, 98% agreed that obesity is a disease, whereas 2% neither agreed nor disagreed. Of the respondents, 53% were familiar with the term “adiposity-based chronic disease” and 13% were certified by the American Board of Obesity Medicine. Of the respondents, 57% used published obesity guidelines as a resource for treating patients with obesity. Most endocrinologists recommended dietary and lifestyle changes, but fewer prescribed an antiobesity medication or recommended bariatric surgery. American Board of Obesity Medicine-certified endocrinologists were more likely to use a multidisciplinary approach.ConclusionSelf-reported knowledge and practices in the management of obesity highlight the importance of a multimodal approach to obesity and foster collaboration among health care professionals. It is necessary to raise awareness about obesity among clinicians, identify knowledge gaps, and create educational tools to address those gaps.     

Current status of long term ventilation of children in the United Kingdom: questionnaire survey

ObjectivesTo identify the number and current location of children, aged 0 to 16 years, requiring long term ventilation in the United Kingdom, and to establish their underlying diagnoses and ventilatory needs.DesignPostal questionnaires sent to consultant respiratory paediatricians and all lead clinicians of intensive care and special care baby units in the United Kingdom.SubjectsAll children in the United Kingdom who, when medically stable, continue to need a mechanical aid for breathing.Results141 children requiring long term ventilation were identified from the initial questionnaire. Detailed information was then obtained on 136 children from 30 units. Thirty three children (24%) required continuous positive pressure ventilation by tracheostomy over 24 hours, and 103 received ventilation when asleep by a non-invasive mask (n=62; 46%), tracheostomy (n=32; 24%), or negative pressure ventilation (n=9; 7%). Underlying conditions included neuromuscular disease (n=62; 46%), congenital central hypoventilation syndrome (n=18; 13%), spinal injury (n=16; 12%), craniofacial syndromes (n=9; 7%), bronchopulmonary dysplasia (n=6; 4%), and others (n=25; 18%). 93 children were cared for at home. 43 children remained in hospital because of home circumstances, inadequate funding, or lack of provision of home carers. 96 children were of school age and 43 were attending mainstream school.ConclusionsA significant increase in the number of children requiring long term ventilation in the United Kingdom has occurred over the past decade. Contributing factors include improved technology, developments in paediatric non-invasive ventilatory support, and a change in attitude towards home care. Successful discharge home and return to school is occurring even for severely disabled patients. Funding and home carers are common obstacles to discharge.

Key messages

• The number of children requiring long term ventilatory support has increased substantially in the past 8 years
• Ventilatory support at home is the best option for meeting the child’s psychological needs and enhancing quality of life
• The majority of children dependent on long term ventilation live at home and attend mainstream schools
• A shift of care has occurred from intensive care units to less acute areas

     

Impact of NHS walk-in centres on the workload of other local healthcare providers: time series analysis

ObjectivesTo assess the impact of NHS walk-in centres on the workload of local accident and emergency departments, general practices, and out of hours services.DesignTime series analysis in walk-in centre sites with no-treatment control series in matched sites.SettingWalk-in centres and matched control towns without walk-in centres in England.Participants20 accident and emergency departments, 40 general practices, and 14 out of hours services within 3 km of a walk-in centre or the centre of a control town.ResultsA reduction in consultations at emergency departments (–175 (95% confidence interval –387 to 36) consultations per department per month) and general practices (–19.8 (−53.3 to 13.8) consultations per 1000 patients per month) close to walk-in centres became apparent, although these reductions were not statistically significant. Walk-in centres did not have any impact on consultations on out of hours services.ConclusionIt will be necessary to assess the impact of walk-in centres in a larger number of sites and over a prolonged period, to determine whether they reduce the demand on other local NHS providers.

What is already known on this topic

One of the objectives for NHS walk-in centres was to reduce demand on other NHS services, particularly general practitioners'' services and accident and emergency departmentsStudies of walk-in centres in North America have indicated that such centres do not reduce demand on other healthcare servicesStudies of minor injuries units in the United Kingdom (which have some similarities with walk-in centres) indicate that these units substitute mainly for consultations in accident and emergency departments

What this study adds

The data imply that walk-in centres may moderate the increasing demand on general practice and reduce the number of consultations in accident and emergency departmentsThe high level of background variability in consultation rates means that any impact of a walk-in centre is not statistically significantTo draw robust conclusions about the impact of walk-in centres on other health providers will require study of a large number of sites over an extended period of time     

Endocrine Involvement in Systemic Amyloidosis

ObjectiveTo present an overview of the published data on endocrine involvement and endocrine dysfunction in patients with systemic amyloidosis.MethodsWe conducted a review of the medical literature using MEDLINE data sources, including clinical trials, in vitro studies, and case reports on pituitary, thyroid, parathyroid, pancreatic, adrenal, and gonadal involvement in systemic amyloidosis.ResultsReports of endocrine involvement in systemic amyloidosis seem to consist primarily of small-samplesize clinical trials or case reports, probably because of the rarity of the disease itself. Systemic amyloidosis mainly involves and causes functional impairment in the thyroid and testes in the endocrine system. Evaluation of adrenal function necessitates special consideration because amyloid infiltration of the adrenal glands resulting in failure may be a life-threatening condition. Amyloid deposition commonly seen in the pituitary gland and the pancreas of patients with Alzheimer disease and type 2 diabetes mellitus, respectively, is generally classified as local amyloidosis and should not be confused with systemic involvement. Additionally, detection of amyloid deposition in the thyroid and testes may have a diagnostic role in patients with suspected systemic or renal amyloidosis.ConclusionPublished data suggest that systemic amyloidosis frequently involves the endocrine system, and endocrine dysfunction seems to be not as rare as previously thought. A rapidly growing goiter or symptoms and signs of adrenal or gonadal dysfunction should raise suspicion of amyloid infiltration. Involvement of pituitary, parathyroid, and pancreatic sites in systemic amyloidosis still remains to be clarified. Further studies with larger sample sizes are needed for complete characterization of the effect of systemic amyloidosis on the endocrine system. (Endocr Pract. 2010;16:1056-1063)