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.

Dissemination of Registered COVID-19 Clinical Trials (DIRECCT): a cross-sectional study.

BACKGROUND: The results of clinical trials should be completely and rapidly reported during public health emergencies such as COVID-19. This study aimed to examine when, and where, the results of COVID-19 clinical trials were disseminated throughout the first 18 months of the pandemic. METHODS: Clinical trials for COVID-19 treatment or prevention were identified from the WHO ICTRP database. All interventional trials with a registered completion date ≤ 30 June 2021 were included. Trial results, published as preprints, journal articles, or registry results, were located using automated and manual techniques across PubMed, Google Scholar, Google, EuropePMC, CORD-19, the Cochrane COVID-19 Study Register, and clinical trial registries. Our main analysis reports the rate of dissemination overall and per route, and the time from registered completion to results using Kaplan-Meier methods, with additional subgroup and sensitivity analyses reported. RESULTS: Overall, 1643 trials with completion dates ranging from 46 to 561 days prior to the start of results searches were included. The cumulative probability of reporting was 12.5% at 3 months from completion, 21.6% at 6 months, and 32.8% at 12 months. Trial results were most commonly disseminated in journals (n = 278 trials, 69.2%); preprints were available for 194 trials (48.3%), 86 (44.3%) of which converted to a full journal article. Trials completed earlier in the pandemic were reported more rapidly than those later in the pandemic, and those involving ivermectin were more rapidly reported than other common interventions. Results were robust to various sensitivity analyses except when considering only trials in a "completed" status on the registry, which substantially increased reporting rates. Poor trial registry data on completion status and dates limits the precision of estimates. CONCLUSIONS: COVID-19 trials saw marginal increases in reporting rates compared to standard practice; most registered trials failed to meet even the 12-month non-pandemic standard. Preprints were common, complementing journal publication; however, registries were underutilized for rapid reporting. Maintaining registry data enables accurate representation of clinical research; failing to do so undermines these registries' use for public accountability and analysis. Addressing rapid reporting and registry data quality must be emphasized at global, national, and institutional levels.

Empirical studies on how ethical recommendations are translated into practice: a cross-section study on scope and study objectives.

BACKGROUND: Empirical research can become relevant for bioethics in at least two ways. First, by informing the development or refinement of ethical recommendations. Second, by evaluating how ethical recommendations are translated into practice. This study aims to investigate the scope and objectives of empirical studies evaluating how ethical recommendations are translated into practice. METHODS: A sample of the latest 400 publications from four bioethics journals was created and screened. All publications were included if they met one of the following three criteria: (1) evaluative empirical research, (2) non-evaluative empirical research and (3) borderline cases. For all publications categorized as evaluative empirical research we analyzed which objects (norms and recommendations) had been evaluated. RESULTS: 234 studies were included of which 54% (n = 126) were categorized as non-evaluative empirical studies, 36% (n = 84) as evaluative empirical studies, and 10% (n = 24) as borderline cases. The object of evaluation were aspirational norms in 5 of the 84 included evaluative empirical studies, more specific norms in 14 (16%) studies and concrete best practices in 65 (77%) studies. The specific best practices can be grouped under five broader categories: ethical procedures, ethical institutions, clinical or research practices, educational programs, and legal regulations. CONCLUSIONS: This mapping study shows that empirical evaluative studies can be found at all stages in the translational process from theory to best practices. Our study suggests two intertwined dimensions for structuring the field of evaluative/translational empirical studies in bioethics: First, three broader categories of evaluation objects and second five categories for types of best practices. TRIAL REGISTRATION: The methodology used was described in a study protocol that was registered publicly on the Open Science Framework ( https://osf.io/r6h4y/ ).

Robust preclinical evidence in somatic cell genome editing: A key driver of responsible and efficient therapeutic innovations.

Somatic cell genome editing (SCGE) is highly promising for therapeutic innovation. This study demonstrates that the majority of 46 preclinical SCGE studies discussed in reviews as particularly promising for clinical translation do not report on key elements for robust and confirmatory research practices: randomization, blinding, sample size calculation, data handling, pre-registration, multi-centric study design, and independent confirmation. We present the here-examined reporting standards and the new National Institutes of Health (NIH) funding criteria for SCGE research as a viable solution to protect this promising field from backlashes. We argue that the implementation of the novel methodological standards provides the opportunity for SCGE research to become a lighthouse example for trustworthy and useful translational research.

Reporting of prior clinical studies in Investigator's Brochures did not adhere to the basic principles of evidence synthesis: a cross-sectional study.

OBJECTIVES: International regulations require Investigator's Brochures (IBs) to compile all available evidence that inform the risk-benefit assessment for the newly planned clinical trial. This study examined the adherence of IBs to the basic principles of evidence synthesis when compiling prior clinical studies. STUDY DESIGN AND SETTING: For 97 IBs for phase I/II trials reviewed at one German research ethics committee we assessed the reporting on search, appraisal, and synthesis procedures for prior clinical studies. For a random subsample of 30 IBs, we evaluated the quality of reporting of the compiled 247 prior clinical studies. RESULTS: Only 2% of all 97 IBs reported a comprehensive search strategy, provided a critical appraisal of the compiled prior clinical studies or presented respective study results in a structured manner. For the 247 prior clinical studies compiled in 30 IBs, the information required to appraise their risk of bias (eg, sample size calculation or baseline characteristics) was rarely reported. CONCLUSION: When compiling all available evidence supporting the rationale for the proposed clinical study IBs do not acknowledge the broadly established principles for reviewing and reporting evidence. This may impact negatively on the trustworthiness and efficiency of risk-benefit assessment.

Practice evaluation of biobank ethics and governance: current needs and future perspectives.

BACKGROUND: Biobank research faces many ethical challenges. Ethics research aims to develop standards for governance to meet these challenges by elaborating overarching normative principles of medical ethics in the context of biobanking. Most ethical standards are widely agreed on among biobank stakeholders and entail specific governance solutions, for example, adoption of consent procedures. In order to fully meet its goal, every governance solution needs to be implemented, evaluated and, if necessary, adapted and improved in practice. This study reviews the scientific literature on biobank ethics and governance in order to identify studies that specifically focus on practice evaluation of biobank governance. METHODS: A PubMed search was carried out. Retrieved literature was categorised and thematically clustered. All studies that focus on practice evaluation were reviewed and their objectives, results, and recommendations for practice summarised. RESULTS: The findings show that the majority of studies on biobank ethics and governance are theoretical; only 25 out of 922 studies empirically evaluate biobank governance in practice. The majority of these (14; 59%) focused on informed consent. Six studies (24%) addressed practice evaluation of sample and data access; the rest focused on public involvement, ethics reporting and incidental findings. Other relevant governance areas such as ethics review, priority setting and sample ownership were not addressed. CONCLUSION: In order to fulfil the ethical goals, more empirical research is needed that provides information on how governance mechanisms perform in practice and what improvements are needed.