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.

Bypassing phase 2 in cancer drug development erodes the risk/benefit balance in phase 3 trials.

OBJECTIVES: Drug developers sometimes launch phase 3 (P3) trials without supporting evidence from phase 2 (P2) trials. We call this practice "P2 bypass." The aims of this study were to estimate the prevalence of P2 bypass and to compare the safety and efficacy results for P3 trials that bypassed with those that did not. STUDY DESIGN AND SETTING: We created a sample of P3 solid tumor trials registered on ClinicalTrials.gov with primary completion dates between 2013 and 2019. We then attempted to match each with a supporting P2 trial using strict and broad criteria. P3 outcomes were meta-analyzed using a random effects model with subgroup contrast between trials that bypassed and those that did not. RESULTS: 129 P3 trial arms met eligibility and nearly half involved P2 bypass. P3 trials involving P2 bypass produced significantly and nonsignificantly worse pooled efficacy estimates using broad and strict matching criteria, respectively. We did not observe significant differences in safety outcomes between P3 trials that bypassed P2 and those that did not. CONCLUSION: The risk/benefit balance of P3 trials that bypassed P2 is less favourable than for trials supported by P2.

Ethical Considerations for Phase I Trials in Oncology.

Phase I trials often represent the first occasion where new cancer strategies are tested in patients. Various developments in cancer biology, methodology, regulation, and medical ethics have altered the ethical landscape of such trials. We provide a narrative review of contemporary ethical challenges in design, conduct, and reporting of phase I cancer trials and outline recommendations for addressing each. We organized our review around four topics, supplementing the first three with scoping reviews: (1) benefit/risk, (2) research biopsies, (3) therapeutic misconception and misestimation, and (4) reporting. The main ethical challenges of conducting phase I trials stem from three issues. First, phase I trials often involve higher research burden and scientific uncertainty compared with other cancer trials. Second, many patients arrive at phase I trials at a transitional point in their illness trajectory where they have exhausted standard survival-extending options. Third, phase I trial results play a major role in informing downstream drug development and regulatory decisions. Together, these issues create distinct pressures for study design, ethical review, informed consent, and reporting. Developments in methodology, regulation, cancer biology, and ethical awareness have helped mitigate some of these challenges, while introducing others. We conclude our review with a series of recommendations regarding trial design, ethical review, consent, and reporting. We also outline several unresolved questions that, if addressed, would strengthen the ethical foundation of phase I cancer trials.

Invasive experimental brain surgery for dementia: Ethical shifts in clinical research practices?

The increasing dementia prevalence worldwide is driving the testing of novel therapeutic approaches, such as invasive brain technologies, despite limited clinical evidence and the risk of accelerating cognitive decline. Our manuscript (a) reviews the NIH Clinicaltrials.gov database for deep brain stimulation, stem cell implantation, and gene therapy trials on people with dementia; (b) discusses issues on beneficence, nonmaleficence, and autonomy associated with these trials; and (c) proposes nine recommendations that build on elements from the Declaration of Helsinki. We found 49 preregistered high-risk trials from nine countries planning to or involving 11,801 people with Alzheimer's or Lewy body dementia or dementia secondary to Parkinson's or Huntington's disease. Most of the people with Alzheimer's who are in these trials are from North America and East Asia. There is substantial heterogeneity in the enrolment criteria, even for trials recruiting only those with Alzheimer's disease. Although most trials enrol people in mild to moderate stages of Alzheimer's disease, trials in China enrol people who have severe Alzheimer's. Our findings highlight a pressing need to review and refine the enrolment criteria for invasive neural trials in people with dementia, considering risks, potential benefits, and capacity for informed consent. As a multidisciplinary team from Australia, the USA, Canada, and Germany with expertise in neurology, neuroscience, and ethics, we examine how it is essential to balance the risks of invasive neural research in a vulnerable population with limited capacity to provide informed consent to help advance the body of knowledge regarding a disease with limited therapeutic options.

Individualized therapy trials: navigating patient care, research goals and ethics.

'Individualized therapy' trials (sometimes called n-of-1 trials) use patients as their own controls to evaluate treatments. Here we divide such trials into three categories: multi-crossover trials aimed at individual patient management, multi-crossover trial series and pre-post trials. These trials all customize interventions for patients; however, the latter two categories also aim to inform medical practice and thus embody tensions between the goals of care and research that are typical of other types of clinical trials. In this Perspective, we discuss four domains where such tensions play out-clinical equipoise, informed consent, reporting and funding, and we provide recommendations for addressing each.

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.

Neuroscientific and Genetic Evidence in Criminal Cases: A Double-Edged Sword in Germany but Not in the United States?

AIM OF THE STUDY: The study examines how neurobiological and genetic explanations of psychopathy influence decision-making of German law students about legal and moral responsibility and sentencing of a defendant in a case of manslaughter. Previous studies from the United States and Germany have been criticized because they partly contradict legal analyses of real-world criminal cases. With a modified design, which integrates the main criticism, we re-examined the impact of biological explanations for psychopathy on decision-making in the courtroom. METHODS: We developed an improved quasi-experimental design to probe three case vignettes presenting different explanations of psychopathy in a criminal case of manslaughter. All three vignettes present the same information about a forensic expert's testimony that is said to report compelling evidence for the diagnosis of "psychopathy." The independent variable being manipulated is the type of information supporting the expert diagnosis: either no biological explanation of "psychopathy" versus a neurological explanation (brain injury) versus a genetic explanation (MAOA gene). The outcome measure is a questionnaire on legal and moral responsibility, free will, the type of custody, and the duration of the sentence. The study is adequately powered. We openly publish the data and all statistical analyses as reproducible R scripts. RESULTS: The answers of German law students (n = 317) indicate that the omission of a neurobiological explanation is significantly associated with higher ratings of legal responsibility while compared to no biological explanation. However, there was no significant difference on the prison sentencing and type of custody assigned. Furthermore, there was no difference in the self-reported impact of the explanation of psychopathy on the participants' decision-making. CONCLUSION: Our findings from German law students corroborates previous research on German judges but is markedly distinct from studies on United States judges. Whereas in the United States, biological information seems to have a mitigating effect, it seems to increase the rate of involuntary commitment to forensic psychiatric hospitals in Germany.

Reader comments to media reports on psychiatric neurosurgery: past history casts shadows on the future.

BACKGROUND: Comments made by readers in response to news articles about current events can provide profound insights into public understanding of and perspectives on those events. Here, in follow up to a paper published last year in this journal, we examined reader comments to articles in newspapers and magazines about neurosurgical interventions for treating psychiatric illness. METHOD: We conducted a thematic analysis of these comments (N = 662 coded units of data) posted in response to 115 newspaper and magazine articles from four countries (Canada, USA, Germany, and Spain) between 2006 and 2017. The comments were coded using an iteratively refined coding scheme that was structured around four a priori categories based on results from the parent study and two new categories that emerged. RESULTS: We found many references to historical psychosurgery and mostly negative and pessimistic comments about ablative neurosurgical interventions. Comments to deep brain stimulation were more positive, and comments to optogenetics most controversial. We also found many expressions of distrust of medical professionals in the context of interventions on the brain and concerns about social and individual control. CONCLUSIONS: Overall, results suggest there is still much work to be done to raise public awareness about re-emerging and new neurosurgical interventions. Balanced discussion is needed if these approaches are to find a place in health care for psychiatric disorders.

Call of Duty at the Frontier of Research: Normative Epistemology for High-Risk/High-Gain Studies of Deep Brain Stimulation.

Research participants are entitled to many rights that may easily come into conflict. The most important ones are that researchers respect their autonomy as persons and act on the principles of beneficence, nonmaleficence, and justice. Since 2014, research subjects from numerous states in the United States of America also have a legal "right to try" that allows them, under certain circumstances, to receive experimental (i.e., preliminarily tested) interventions, including medical devices, before official approval from the United States Food and Drug Administration. In the context of experimental interventions, such as deep brain stimulation (DBS) for Alzheimer's disease, this article argues that research participants ought never to have a legal "right to try" without a corresponding "right to be sure." The latter refers to external epistemic justification construed in terms of reliance on reliable evidence. This article demonstrates that the mere complexity of intervention ensembles, as in the case of DBS for Alzheimer's disease which serves as a paradigm example, illustrate how unanswered and/or unasked open questions give rise to a "combinatorial explosion" of uncertainties that require epistemic responses that no single research team alone is likely able to provide. From this assessment, several epistemic asymmetrical relations between researchers and participants are developed. By elucidating these epistemic asymmetries, this article unravels the reasons why open science, transparent exhaustive data reporting, preregistration, and continued constant critical appraisal via pre- and postpublication peer review are not scientific virtues of moral excellence but rather ordinary obligations of the scientific work routine required to increase reliability and strength of evidence.

Opening the debate on deep brain stimulation for Alzheimer disease - a critical evaluation of rationale, shortcomings, and ethical justification.

BACKGROUND: Deep brain stimulation (DBS) as investigational intervention for symptomatic relief from Alzheimer disease (AD) has generated big expectations. Our aim is to discuss the ethical justification of this research agenda by examining the underlying research rationale as well as potential methodological pitfalls. The shortcomings we address are of high ethical importance because only scientifically valid research has the potential to be ethical. METHOD: We performed a systematic search on MEDLINE and EMBASE. We included 166 publications about DBS for AD into the analysis of research rationale, risks and ethical aspects. Fifty-eight patients were reported in peer-reviewed journals with very mixed results. A grey literature search revealed hints for 75 yet to be published, potentially enrolled patients. RESULTS: The results of our systematic review indicate methodological shortcomings in the literature that are both scientific and ethical in nature. According to our analysis, research with human subjects was performed before decisive preclinical research was published examining the specific research question at stake. We also raise the concern that conclusions on the potential safety and efficacy have been reported in the literature that seem premature given the design of the feasibility studies from which they were drawn. In addition, some publications report that DBS for AD was performed without written informed consent from some patients, but from surrogates only. Furthermore, registered ongoing trials plan to enroll severely demented patients. We provide reasons that this would violate Art. 28 of the Declaration of Helsinki, because DBS for AD involves more than minimal risks and burdens, and because its efficacy and safety are not yet empirically established to be likely. CONCLUSION: Based on our empirical analysis, we argue that clinical research on interventions of risk class III (Food and Drug Administration and European Medicines Agency) should not be exploratory but grounded on sound, preclinically tested, and disease-specific a posteriori hypotheses. This also applies to DBS for dementia as long as therapeutic benefits are uncertain, and especially when research subjects with cognitive deficits are involved, who may foreseeably progress to full incapacity to provide informed consent during the required follow-up period.

The re-emergence of psychiatric neurosurgery: insights from a cross-national study of newspaper and magazine coverage.

BACKGROUND: Surgical approaches to treat psychiatric disorders have made a comeback. News media plays an essential role in exposing the public to trends in health care such as the re-emergence of therapeutic interventions in psychiatric neurosurgery that were set aside for decades, and in shaping attitudes and acceptance to them. METHOD: We conducted an analysis of media articles covering all types of psychiatric neurosurgery published in Canada, USA, Germany, and Spain between the years 1960 and 2015. We applied both quantitative and qualitative methods to elucidate patterns of reporting for conditions, themes and tone, across geographic regions, time, and for type of intervention. RESULTS: Coverage of psychiatric neurosurgery has surged since 2001 and is largely consistent across the countries examined. It focuses on depression and deep brain stimulation, and is explicit about historical context. The tone of coverage becomes more positive for Canada, USA and Spain over time; the tone of coverage from Germany remains cautious. Identity and privacy are among the few ethical and philosophical issues raised, notably in the German press. CONCLUSIONS: The focused and optimistic attention to contemporary psychiatric neurosurgery in the media, but inattention to ethical issues, places an extra burden on functional neurosurgeons, psychiatrists, and other frontline health professionals to attend to queries from patients and policy makers about the full range of relevant emergent and emerging interventions and the mental health issues to which they may beneficially apply.

Ethical Considerations for Deep Brain Stimulation Trials in Patients with Early-Onset Alzheimer's Disease.

Several studies of deep brain stimulation (DBS) of the fornix or the nucleus basalis of Meynert have been recently conducted in people with Alzheimer's disease, with several recruiting participants <65 and thus have early-onset Alzheimer's disease (EOAD). Although EOAD accounts for less than 5.5% of AD cases, ethical considerations must still be made when performing DBS trials including these participants since a portion of people with EOAD, especially those possessing autosomal-dominant mutations, have an atypical and more aggressive disease progression. These considerations include appropriate patient selection and signing of an informed consent for genetic testing; appropriate study design; potential outcomes that people with EOAD could expect; and accurate interpretation and balanced discussion of trial results. Finally, recommendations for future DBS for AD trials will be made to ensure that EOAD patients will not experience avoidable harms should they be enrolled in these experimental studies.