Characteristics and Research Waste Among Randomized Clinical Trials in Gastric Cancer.

Importance: The results of numerous large randomized clinical trials (RCTs) have changed clinical practice in gastric cancer (GC). However, research waste (ie, unpublished data, inadequate reporting, or avoidable design limitations) is still a major challenge for evidence-based medicine. Objectives: To determine the characteristics of GC RCTs in the past 20 years and the presence of research waste and to explore potential targets for improvement. Design, Setting, and Participants: In this cross-sectional study of GC RCTs, ClinicalTrials.gov was searched for phase 3 or 4 RCTs registered from January 2000 to December 2019 using the keyword gastric cancer. Independent investigators undertook assessments and resolved discrepancies via consensus. Data were analyzed from August through December 2020. Main Outcomes and Measures: The primary outcomes were descriptions of the characteristics of GC RCTs and the proportion of studies with signs of research waste. Research waste was defined as unpublished data, inadequate reporting, or avoidable design limitations. Publication status was determined by searching PubMed and Scopus databases. The adequacy of reporting was evaluated using the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline checklist. Avoidable design limitations were determined based on existing bias or lack of cited systematic literature reviews. In the analyses of research waste, 125 RCTs that ended after June 2016 without publication were excluded. Results: A total of 262 GC RCTs were included. The number of RCTs increased from 25 trials in 2000 to 2004 to 97 trials in 2015 to 2019, with a greater increase among RCTs of targeted therapy or immunotherapy, which increased from 0 trials in 2000 to 2004 to 36 trials in 2015 to 2019. The proportion of RCTs that were multicenter was higher in non-Asian regions than in Asian regions (50 of 71 RCTs [70.4%] vs 96 of 191 RCTs [50.3%]; P = .004). The analysis of research waste included 137 RCTs, of which 81 (59.1%) were published. Among published RCTs, 65 (80.2%) were judged to be adequately reported and 63 (77.8%) had avoidable design defects. Additionally, 119 RCTs (86.9%) had 1 or more features of research waste. Study settings that included blinding (odds ratio [OR], 0.56; 95% CI, 0.33-0.93; P = .03), a greater number of participants (ie, ≥200 participants; OR, 0.07; 95% CI, 0.01-0.51; P = .01), and external funding support (OR, 0.22; 95% CI, 0.08-0.60; P = .004) were associated with lower odds of research waste. Additionally, 35 RCTs (49.3%) were referenced in guidelines, and 18 RCTs (22.2%) had their prospective data reused. Conclusions and Relevance: To our knowledge, this study is the first to describe the characteristics of GC RCTs in the past 20 years, and it found a research waste burden, which may provide evidence for the development of rational RCTs and reduction of waste in the future.

Improving the evaluation of COPD exacerbation treatment effects by accounting for early treatment discontinuations: a post-hoc analysis of randomized clinical trials.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) clinical trials aimed at evaluating treatment effects on exacerbations often suffer from early discontinuations of randomized treatment. Treatment discontinuations imply a loss of information and should ideally be considered in the statistical analysis of trial results, particularly if the discontinuations are related to the disease or treatment itself. Here, we explore this issue by investigating (1) whether there exists an association between the risks of exacerbation and treatment discontinuation in COPD clinical trials and (2) whether disregarding this association can cause bias in exacerbation treatment effect estimates. We focus on the hypothetical estimand, i.e. the treatment effect that would have been observed had all subjects completed the trial as planned. METHODS: The association between exacerbation and discontinuation risks was analysed by applying a joint frailty (random effect) model - allowing for the simultaneous analysis of multiple types of correlated events - to data from five Phase III-IV COPD clinical trials. Specifically, the impact of the association on exacerbation treatment effect estimates was assessed by comparing the treatment hazard ratios of the joint frailty model to the rate/hazard ratios of two related statistical models (the negative binomial and shared frailty models), which both assume discontinuations to be unrelated to the trial outcome. The models were also compared using simulated data. RESULTS: A statistically significant (p < 0.0001), positive association between exacerbation and discontinuation risks was found in all trials. Importantly, simulations confirmed that - with such an association - models disregarding the association risk producing biased results (> 5 percentage point difference in hazard/rate ratio). For some treatment comparisons in the clinical trials, the difference in treatment effect estimates between the joint frailty and the other models was as high as 10-15 percentage points. The difference was affected by the strength of the exacerbation-discontinuation association, the population heterogeneity in exacerbation risk, and the difference in discontinuation rates between treatment arms. CONCLUSIONS: We have identified an association between the risks of exacerbation and treatment discontinuation in five COPD clinical trials. We recommend using the joint frailty model to account for this association when estimating exacerbation treatment effects, particularly when targeting the hypothetical estimand.

Use of Both Qualitative and Quantitative Methods to Estimate Meaningful Change Thresholds for Key Endpoints in Pediatric Asthma Trials.

INTRODUCTION: Diary-derived symptom score and rescue medication use endpoints, such as symptom-free days (SFDs) and rescue medication-free days (RFD), are frequently used as clinical trial endpoints. Estimates of meaningful change for SFDs and RFDs have not been generated in pediatric populations. This research aimed to generate evidence supporting estimates of the individual within-patient changes that constitute an important or meaningful change in SFDs, RFDs, and updated estimates on the Childhood Asthma Control Test (C-ACT) in pediatric asthma populations aged 5-11 years. METHODS: Semistructured, qualitative interviews were conducted with children (ages 8-11 years) who had asthma and parents/caregivers of children (4-11 years) with asthma. Before the interview (4-9 days) participants were asked to complete a morning and evening diary. RESULTS: On average, parent/caregiver estimates of the difference in SFDs between a "very bad" and a "little bad" week for their children's asthma were largely concordant with the values reported by their children (differences of 1.8 and 1.4 SFDs, respectively). Both parents/caregivers and children were able to articulate what a meaningful level of change would be on the C-ACT at the item level. This qualitative study generated C-ACT item-level meaningful change estimates in the region of 1-3 category change, which potentially suggests that, if scaled up to represent C-ACT total score, this would lead to change estimates of 7-15 points. CONCLUSIONS: Our findings suggest that both children with asthma and parents/caregivers can quantitatively estimate and to some extent qualitatively articulate meaningful change in SFDs and RFDs.

SCORE-IT (Selecting Core Outcomes for Randomised Effectiveness trials In Type 2 diabetes): a systematic review of registered trials.

BACKGROUND: Outcomes measured in clinical trials should be meaningful to patients, healthcare professionals and researchers, yet there is heterogeneity in the outcomes used across trials. This inconsistency impacts on the ability to compare findings and may mean that the results have little importance to healthcare professionals and the patients that they care for. The aim of the present study is to review the outcomes used in registered trials of therapies for type 2 diabetes mellitus as the first step in the development of a core outcome set for effectiveness trials in type 2 diabetes. METHODS: A systematic review of clinicaltrials.gov entries was completed for randomised, open (actively recruiting or in follow-up period), phase 3 and 4 trials of type 2 diabetes mellitus in adults. Trials of the treatment of diabetes complications, co-morbidities, prevention and surgery were excluded. Each trial was screened for eligibility and outcomes extracted from the primary and secondary outcomes data fields and free text study information. The outcomes were recorded verbatim and classified into core outcome domains according to the COMET taxonomy. RESULTS: A total of 354 trial registrations were reviewed for eligibility and 138 trials included. In total, 1444 outcomes were extracted with a median of eight outcomes per trial (range = 1-60). Outcomes were categorised into 30 different outcome domains according to the COMET taxonomy, but no single domain or outcome was measured in 100% of trials. The majority of trials (88%) included outcomes in the 'metabolism and nutrition' domain, such as lipids and lipoproteins (21%), HbA1c (18%), hypoglycaemia (14%), fasting plasma/blood glucose (11%), glycaemic variability (8%), postprandial response (8%) and insulin sensitivity (5%). Only 10% of trials included one or more patient reported outcomes; of these, 29% included the Diabetes Treatment Satisfaction Questionnaire. CONCLUSIONS: There is marked heterogeneity in the outcomes measured in registered therapeutic intervention trials for type 2 diabetes. The use of an agreed set of core outcomes will improve the consistency of reporting in clinical trials for type 2 diabetes. TRIAL REGISTRATION: The core outcome set study, of which this is a part, is registered in the COMET database, http://www.comet-initiative.org/studies/details/956 . Registered on 24 January 2017.

Phase IV implementation studies. The forgotten finale to the complex intervention methodology framework.

The complex intervention methodology framework defines the iterative process for developing and evaluating complex interventions in healthcare, but advice on implementation research was not included until the 2008 update. Our recent systematic review of implementation studies identified significant problems with reporting standards, including inconsistent terminology and crucial information that was missing or unclear. Introduction of reporting checklists has standardized the reporting of randomized controlled trials and other types of studies, and there is a need for similar guidance for reporting implementation studies. Key standards might include an explicit evidence base from a randomized controlled trial or guideline recommendation; recruitment to the clinical service, not the research; at least some outcomes at the population level using routinely collected data; and a description of the setting and the process of implementing the service. The complex intervention framework currently illustrates a cycle of development and evaluation, which includes implementation as a final step. We propose that the research underpinning implementation should be visualized as a second interrelated cycle. Just as the "phase III cycle" includes the iterative steps of development and piloting, a similar process may be needed to translate the intervention into a practical service that can be tested in a phase IV implementation study.

Phase 4 research: what happens when the rubber meets the road?

Approval of a novel drug is oftentimes seen as the end of the development pathway. However, the appearance of rare but serious side effects in patients taking approved drugs has led to increased attention to phase 4, or postmarketing, research. Traditionally, postmarketing research relied on reports from clinicians to monitor for unexpected toxicity. However, such reporting will produce a biased assessment of risk due to underreporting of toxic effects in older medications. The availability of large, representative databases and more flexible analysis tools has led to comprehensive and near "real-time" surveillance programs. These programs have been used by the US Food and Drug Administration to explore toxicities of approved medications. The need for effective tools with which to monitor clinically relevant outcome events has been further increased by the development of accelerated pathways to drug approval. In areas without effective treatments, such pathways lead to licensure without rigorous clinical efficacy data. Continued approval is frequently made contingent on the availability of postmarketing surveillance data demonstrating improvements in clinical end points and these data can also be used to monitor for unexpected toxicity.

Exclusion of pregnant women from industry-sponsored clinical trials.

OBJECTIVE: The lack of human data available to inform evidence-based treatment for illness during pregnancy has led to calls for greater inclusion of pregnant women in research, but the extent of their current representation is poorly characterized. Our objective was to measure the current exclusion of pregnant women from industry-sponsored clinical trials as a baseline for future comparison. METHODS: We compiled data from studies enrolling women of childbearing potential posted on www.ClinicalTrials.gov between 1 October 2011 and 31 January 2012. The review was limited to open United States-based phase IV interventional studies sponsored by the pharmaceutical industry evaluating treatment of conditions that may be experienced by but are not limited to pregnant women and did not involve a medication classified as potentially teratogenic. If there was no mention of pregnancy in the inclusion or exclusion criteria, we contacted a study representative to confirm that pregnant women could be enrolled. RESULTS: Of 558 qualifying industry-sponsored studies, five (1%) were designed specifically for pregnant women. Of 367 phase IV clinical trials with verified inclusion and exclusion criteria, 348 (95%) excluded pregnant women and 19 (5%) did not. CONCLUSION: We found the exclusion of pregnant women from industry-sponsored clinical trials to be common practice. Moving beyond reflexive exclusion and developing thoughtful criteria for inclusion of pregnant women in clinical research would likely advance the evidence base to inform treatment decisions during pregnancy and lead to better health outcomes for women and children.

Screening intervention to identify eligible patients and improve accrual to phase II-IV oncology clinical trials.

PURPOSE: Low enrolment rates in clinical trials present a barrier to the development of novel cancer therapies. Currently, only 3% of patients with cancer participate, and many studies fail to achieve necessary enrolment. The objective of this study was to evaluate whether a screening intervention to identify potentially eligible patients (PEPs) would increase accrual rates. PATIENTS AND METHODS: Over a 4-month intervention period, PEPs for 21 phase II-IV breast, gastrointestinal, genitourinary, gynecology, and lung cancer trials were identified by a screening coordinator. This individual reviewed the electronic medical records of patients attending outpatient clinics and flagged PEPs for 10 medical oncologists at the BC Cancer Agency. Patients who were already documented to be trial eligible by physicians were not flagged. Oncologists were surveyed regarding the helpfulness and accuracy of the intervention. RESULTS: During the intervention period, 73 patients were enrolled, compared with 61 patients enrolled in the 4 months prior and 51 patients in the 4 months after. A total of 2,098 charts were reviewed, and 120 PEPs were identified during the intervention period, resulting in 19 PEPs who enrolled and four PEPs who declined a clinical trial. Relative accrual rates adjusted for oncologist appointments were 0.85 (P = .15) before and 0.70 (P < .005) after, relative to the intervention period. Oncologist-returned surveys indicated that 67% of flags were helpful, and 70% were accurate. CONCLUSIONS: In this study, manually screening patient records increased enrolment to specific clinical trials. A screening intervention process, involving a dedicated screening coordinator, should be considered to improve clinical trial accrual.

Phase IV non-inferiority trials and additional claims of benefit.

BACKGROUND: Non-inferiority (NI) trials in drug research are used to demonstrate that a new treatment is not less effective than an active comparator. Since phase IV trials typically aim at informing a clinical decision, the value of a phase IV non-inferiority trial hinges also on its clinical relevance. In such trials, clinical relevance would refer to the added benefit claims of a specific drug, apart from efficacy, relative to its comparator drug in the trial. METHODS: In this study, we reviewed 41 phase IV trials and extracted information on whether the authors mentioned any additional benefit beyond the NI (efficacy) claim of the drug and whether the additional benefit was proven in the trial. We checked whether the additional claim was based on descriptions only or on formal statistical analyses. RESULTS: Our results showed that 22 out of the 41 NI trials mentioned additional benefit of the test drug and most of these claims were related to the safety profile. Of all the post-authorization NI trials that claimed additional benefit, 10 out of 22 NI trials used formal statistical analyses to show additional benefit, and only one included a sample size calculation for the additional benefit prior to the trial. CONCLUSION: We conclude that there is room for improvement in terms of designing phase IV NI trials with added benefit claims and in proving these additional claims.

[The GCP directive--consequences for clinical drug research]. / GCP-direktivet--konsekvenser for klinisk laegemiddelforskning.

The contents and implications of the EU Directive on good clinical (research) practice (GCP) regarding drug trials are described. As of May 2003, clinical researchers in Denmark must have standard operation procedures, conduct monitoring, consider quality assurance, and expect inspections. The industry may be better prepared, but the Directive makes GCP part of the law and phase IV studies become subject to GCP. Patients will be assured the same quality in trials irrespective of the industry or investigator being the sponsor and may look forward to quality improvement of drug trials.

Problems with publishing results of interim analyses of randomized clinical trials.

PURPOSE: This purpose of this study was to illustrate how publication of interim analyses of randomized clinical trials (RCTs) can cause problems in the interpretation of final results. METHOD: The effect of publishing interim analyses on the results of a typical HIV RCT comparing regimens of registered antiretroviral drugs was illustrated using a simulation study. Simulations modeled an RCT comparing the effect of two treatment combinations on changes in log HIV viral load from baseline. Publication of interim results at 6 months was assumed to lead to 50% of patients switching from the poorer treatment if interim results were statistically significant (p <.05), 20% of patients switching from the poorer treatment if interim results were marginally significant (.05 < p <.20), and 10% of all patients switching treatment if interim results were not statistically significant. Three scenarios were simulated: a large treatment difference (0.4 log HIV viral load), a moderate difference (0.2 log), and no treatment difference (0.0 log). RESULTS: The simulation study showed that if the true treatment difference was large (0.4 log) the power of the trial was reduced from over 80% at 6 months to under 37% at 12 months. Furthermore, given the statistical significance of the interim analysis results at 6 months, the simulations illustrated that the trial results would appear similar at 12 months, regardless of the true underlying treatment difference. CONCLUSION: The simulations reinforce the fact that publication of interim analyses of RCTs can affect the future conduct of a trial and make interpretation of final results difficult.

[Ethics problems in phase IV of drug studies]. / Problemi etici nella fase IV degli studi sui farmaci.

Phase IV clinical studies include all investigations carried out after the approval of drugs. The objective of these studies is well defined: to gain additional knowledge on efficacy and safety of drugs. There are uncertainties however with regard to which kind of study design is appropriate to provide scientifically valid contributions. In the present article we will clarify why an experimental design (e.g. randomized clinical trial) is ordinarily required, on the basis of scientific and ethical concerns, to answer questions concerning efficacy even after drug commercialization. Viceversa, non experimental designs (from case series analysis to cohort and case control studies) are indicated to investigate drug effects in current practice if the objective is to evaluate safety.

Guidelines for the implementation of drug utilization observation (DUO) studies in psychopharmacological therapy. The "Phase IV Research" Task-Force of the Association for Neuropsychopharmacology and Pharmacopsychiatry (AGNP).

The task-force on Phase-IV-Research of the Association for Neuropharmacology and Pharmacopsychiatry (AGNP) has developed guidelines for the implementation of scientifically sound drug utilisation observation studies (DUO studies). These guidelines have been adopted by the executive committee as the position of the association. DUO studies are prospective pharmacoepidemiological studies, by which prescription, illness, and patient data of individual patients are collected without interference with the routine course of treatment. They can answer questions on the interaction of treatment modalities with positive and negative treatment outcome. Scientific standards require that there is a study protocol which describes the epidemiological, statistical, procedural, and quality assurance methodology and states who is responsible for what. As such studies can violate data protection regulations or can be used for sales instead of scientific purposes, consultation of an ethics committee is recommended.