Informed consent and trial prioritization for clinical studies during the COVID-19 pandemic. Stakeholder experiences and viewpoints.

BACKGROUND: Very little is known about the practice-oriented challenges and potential response strategies for effective and efficient translation of informed consent and study prioritization in times of a pandemic. This stakeholder interview study aimed to identify the full spectrum of challenges and potential response strategies for informed consent and study prioritization in a pandemic setting. METHODS: We performed semi-structured interviews with German stakeholders involved in clinical research during the COVID-19 pandemic. We continued sampling and thematic text analysis of interview transcripts until thematic saturation of challenges and potential response strategies was reached. RESULTS: We conducted 21 interviews with investigators, oversight bodies, funders and research support units. For the first topic informed consent we identified three main themes: consent challenges, impact of consent challenges on clinical research, and potential strategies for consent challenges. For the second topic prioritization of clinical studies, we identified two main themes: perceived benefit of prioritization and potential strategies for prioritization. All main themes are further specified with subthemes. A supplementary table provides original quotes from the interviews for all subthemes. DISCUSSION: Potential response strategies for challenges with informed consent and study prioritization partly share common ground. High quality procedures for study prioritization, for example, seem to be a core response strategy in dealing with informed consent challenges. Especially in a research environment with particularly high uncertainty regarding potential treatment effects and further limitations for valid informed consent should the selection of clinical trials be very well justified from a scientific, medical, and ethics viewpoint.

Research encouraging off-label use of quetiapine: A systematic meta-epidemiological analysis.

BACKGROUND: Researchers often conduct small studies on testing a drug's efficacy in off-label indications. If positive results from these exploratory studies are not followed up by larger, randomized, double-blinded trials, physicians cannot be sure of a drug's clinical value. This may lead to off-label prescriptions of ineffective treatments. We aim to describe the way clinical studies fostered off-label prescription of the antipsychotic drug quetiapine (Seroquel). METHODS: In this systematic meta-epidemiological analysis, we searched EMBASE, MEDLINE, Cochrane CENTRAL and PsycINFO databases and included clinical studies testing quetiapine for unapproved indications between May 1995 and May 2022. We then assessed the frequency with which publications providing low-level evidence suggesting efficacy of quetiapine for off-label indications was not followed up by large, randomized and double-blinded trials within 5 years. RESULTS: In total, 176 published studies were identified that reported potential efficacy of quetiapine in at least 26 indications. Between 2000 and 2007, publication of exploratory studies suggesting promise for off-label indications rapidly outpaced publication of confirmatory trials. In the 24 indications with a minimum of 5 years of follow-up from the first positive exploratory study, 19 (79%) were not followed up with large confirmatory trials within 5 years. At least nine clinical practice guidelines recommend the use of quetiapine for seven off-label indications in which published confirmatory evidence is lacking. CONCLUSION: Many small, post-approval studies suggested the promise of quetiapine for numerous off-label indications. These findings generally went unconfirmed in large, blinded, randomized trials years after first being published. The imbalance of exploratory and confirmatory studies likely encourages ineffective off-label treatment.

Reporting of patient involvement: a mixed-methods analysis of current practice in health research publications using a targeted search strategy.

OBJECTIVES: To evaluate the extent and quality of patient involvement reporting in examples of current practice in health research. DESIGN: Mixed-methods study. We used a targeted search strategy across three cohorts to identify health research publications that reported patient involvement: original research articles published in 2019 in the British Medical Journal (BMJ), articles listed in the Patient-Centered Outcomes Research Institute (PCORI) database (2019), and articles citing the GRIPP2 (Guidance for Reporting Involvement of Patients and Public) reporting checklist for patient involvement or a critical appraisal guideline for user involvement. Publications were coded according to three coding schemes: 'phase of involvement', the GRIPP2-Short Form (GRIPP2-SF) reporting checklist and the critical appraisal guideline. OUTCOME MEASURES: The phase of the study in which patients were actively involved. For the BMJ sample, the proportion of publications that reported patient involvement. The quality of reporting based on the GRIPP2-SF reporting guideline. The quality of patient involvement based on the critical appraisal guideline. Quantitative and qualitative results are reported. RESULTS: We included 86 publications that reported patient involvement. Patients were most frequently involved in study design (90% of publications, n=77), followed by study conduct (71%, n=61) and dissemination (42%, n=36). Reporting of patient involvement was often incomplete, for example, only 40% of publications (n=34) reported the aim of patient involvement. While the methods (57%, n=49) and results (59%, n=51) of involvement were reported more frequently, reporting was often unspecific and the influence of patients' input remained vague. Therefore, a systematic assessment of the quality and impact of patient involvement according to the critical appraisal guideline was not feasible across samples. CONCLUSIONS: As patient involvement is increasingly seen as an integral part of the research process and requested by funding bodies, it is essential that researchers receive specific guidance on how to report patient involvement activities. Complete reporting builds the foundation for assessing the quality of patient involvement and its impact on research.

Preclinical efficacy in investigator's brochures: Stakeholders' views on measures to improve completeness and robustness.

AIMS: Research ethics committees and regulatory agencies assess whether the benefits of a proposed early-stage clinical trial outweigh the risks based on preclinical studies reported in investigator's brochures (IBs). Recent studies have indicated that the reporting of preclinical evidence presented in IBs does not enable proper risk-benefit assessment. We interviewed different stakeholders (regulators, research ethics committee members, preclinical and clinical researchers, ethicists, and metaresearchers) about their views on measures to increase the completeness and robustness of preclinical evidence reporting in IBs. METHODS: This study was preregistered (https://osf.io/nvzwy/). We used purposive sampling and invited stakeholders to participate in an online semistructured interview between March and June 2021. Themes were derived using inductive content analysis. We used a strengths, weaknesses, opportunities and threats matrix to categorize our findings. RESULTS: Twenty-seven international stakeholders participated. The interviewees pointed to several strengths and opportunities to improve completeness and robustness, mainly more transparent and systematic justifications for the included studies. However, weaknesses and threats were mentioned that could undermine efforts to enable a more thorough assessment: The interviewees stressed that current review practices are sufficient to ensure the safe conduct of first-in-human trials. They feared that changes to the IB structure or review process could overburden stakeholders and slow drug development. CONCLUSION: In principle, more robust decision-making processes align with the interests of all stakeholders and with many current initiatives to increase the translatability of preclinical research and limit uninformative or ill-justified trials early in the development process. Further research should investigate measures that could be implemented to benefit all stakeholders.

Non-Specific Low Back Pain.

BACKGROUND: For many years, low back pain has been both the leading cause of days lost from work and the leading indication for medical rehabilitation. The goal of the German Disease Management Guideline (NDMG) on nonspecific low back pain is to improve the treatment of patients with this condition. METHODS: The current update of the NDMG on non-specific low back pain is based on articles retrieved by a systematic search of the literature for systematic reviews. Its recommendations for diagnosis and treatment were developed by a collaborative effort of 29 scientific medical societies and organizations and approved in a formal consensus process. RESULTS: If the history and physical examination do not arouse any suspicion of a dangerous underlying cause, no further diagnostic evaluation is indicated for the time being. Passive, reactive measures should be taken only in combination with activating measures, or not at all. When drugs are used for symptomatic treatment, patients should be treated with the most suitable drug in the lowest possible dose and for as short a time as possible. CONCLUSION: A physician should be in charge of the overall care process. The patient should be kept well informed over the entire course of his or her illness and should be encouraged to adopt a healthful lifestyle, including regular physical exercise.

The Prevention and Treatment of Retinal Complications in Diabetes.

BACKGROUND: Microvascular complications of diabetes mellitus can cause retino pathy and maculopathy, which can irreversibly damage vision and lead to blindness. The prevalence of retinopathy is 9-16% in patients with type 2 diabetes and 24-27% in patients with type 1 diabetes. 0.2-0.5% of diabetics are blind. METHODS: The National Disease Management Guideline on the prevention and treatment of retinal complications in diabetes was updated according to recommendations developed by seven scientific medical societies and organizations and by patient representatives and then approved in a formal consensus process. These recommendations are based on international guidelines and systematic reviews of the literature. RESULTS: Regular ophthalmological examinations enable the detection of retinopathy in early, better treatable stages. The control intervals should be based on the individual risk profile: 2 years for low-risk patients and 1 year for others, or even shorter depending on the severity of retinopathy. General risk factors for retinopathy include the duration of diabetes, the degree of hyperglycemia, hypertension, and diabetic nephropathy. The general, individually adapted treatment strategies are aimed at improving the risk profile. The most important specifically ophthalmological treatment recommendations are for panretinal laser coagulation in proliferative diabetic retinopathy and, in case of clinically significant diabetic macular edema with foveal involvement, for the intravitreal application of medications (mainly, vascular endothelial growth factor [VEGF] inhibitors), if an improvement of vision with this treatment is thought to be possible. CONCLUSION: Regular, risk-adapted ophthalmological examinations, with standardized documentation of the findings for communication between ophthalmologists and the patients' treating primary care physicians/diabetologists, is essential for the prevention of diabetic retinal complications, and for their optimal treatment if they are already present.