Publication Of Trial Results Research Articles

Outcome Reporting Bias in Clinical Trials Researching Disease-Modifying Therapy in Patients With Multiple Sclerosis.

Outcome reporting bias occurs when publication of trial results is dependent on clinical significance, thereby threatening the validity of trial results. Research on immunomodulatory drugs in multiple sclerosis has thrived in recent years. We aim to comprehensively examine to what extent outcome reporting bias is present in these trials and the possible underlying factors. We identified clinical trials evaluating the efficacy and safety of immunomodulatory drugs in patients with multiple sclerosis (MS) registered in ClinicalTrials.gov after September 2007 and completed before the end of 2018. Information about study design, type of funding, and primary and secondary outcome measures was extracted from the registry. Timing of registration in relation to study initiation and subsequent amendments to the planned outcomes were reviewed. Publications related to these trials were identified in several bibliographic databases using the trial registration number. Registered primary and secondary outcomes were recorded for each trial and compared with outcomes in the publication describing the main outcomes of the trial. A search of ClinicalTrials.gov identified 535 eligible registered clinical trials; of these, 101 had a matching publication. Discrepancies between registered and published primary and secondary outcomes were found in 95% of the trials, including discrepancies between the registered and published primary outcomes in 26 publications. Forty-four percent of the published secondary outcomes were not included in the registry. A similar proportion of registered and nonregistered reported primary efficacy outcomes were positive (favoring the intervention). Nonindustry-funded and open-label trials in MS were more prone to selective primary outcome reporting, although these findings did not reach statistical significance. Only two-thirds of the trials were registered in ClinicalTrials.gov before the trial start date, and 62% of trials made amendments in registered outcomes during or after the trial period. Selective outcome reporting is prevalent in trials of disease-modifying drugs in people with MS. We propose methods to diminish the occurrence of this bias in future research.

Data Dissemination of the Role of Neoadjuvant Radiation in Retroperitoneal Sarcoma: A CTOS and CSSO Survey.

Consensus guidelines call for complete resection of retroperitoneal sarcoma with consideration of neoadjuvant radiation for curative-intent treatment. The 15-month delay from the initial presentation of an abstract to the final publication of the STRASS trial results assessing the impact of neoadjuvant radiation led to a dilemma of how patients should be managed in the interim. This study aims to (1) understand perspectives regarding neoadjuvant radiation for RPS during this period; and (2) assess the process of integrating data into practice. A survey was distributed to international organizations including all specialties treating RPS. Eighty clinicians responded, including surgical (60.5%), radiation (21.0%) and medical oncologists (18.5%). Low kappa correlation coefficients on a series of clinical scenarios querying individual recommendations before and after initial presentation as an abstract indicate considerable change. Over 62% of respondents identified a practice change; however, most also noted discomfort in adopting changes without a manuscript available. Of the 45 respondents indicating discomfort with practice changes without a full manuscript, 28 (62%) indicated that their practice changed in response to the abstract. There was substantial variability in recommendations for neoadjuvant radiation between the presentation of the abstract and the publication of trial results. The difference in the proportion of clinicians describing comfort with changing practice based on the presentation of the abstract versus those that had done so shows that indications for proper integration of data into practice are not clear. Endeavors to resolve this ambiguity and expedite availability of practice-changing data are warranted.

Patient consent to publication and data sharing in industry and NIH-funded clinical trials

BackgroundParticipants are recruited into clinical trials under the assumption that the research will contribute to medical knowledge. Therefore, non-publication trials—and, more recently, lack of data sharing—are widely considered to violate the trust of trial participants. Existing practices regarding patient consent to publication and data sharing have not been evaluated. Analyzing informed consent forms (ICFs), we studied what trial participants were told regarding investigators’ intention to contribute to medical knowledge, publish trial results, and share de-identified trial data.MethodsWe obtained 98 ICFs of industry-funded pre-marketing trials for all (17) antibiotics approved by the European Medicines Agency and 46 ICFs of publicly funded trials from the National Heart, Lung and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) data repository. Three authors independently reviewed ICFs to identify and extract what was stated or implied regarding: (1) publication of results; (2) sharing de-identified data; (3) data ownership; (4) confidentiality of identifiable data; and (5) whether the trial will produce knowledge that offers public benefit. Consensus was obtained from the two reviewers with the greatest overall agreement on all five measures. Disagreements were resolved through discussion among all authors.ResultsFour (3%) trials indicated a commitment to publish trial results; 140 (97%) did not commit to publishing trial results; six (4%) indicated a commitment to share de-identified data with third party researchers. Commitments to share were more common in publicly funded trials than industry-funded trials (7% vs 3%). A total of 103 (72%) ICFs indicated the trials will or may produce knowledge that offers public benefits, while 131 (91%) ICFs left unstated who “owned” trial data; of those with statements, the sponsor always claimed ownership. Patient confidentiality was guaranteed in 137 (95%) trials.ConclusionsOur results suggest that consent forms rarely disclose investigators’ intentions regarding the sharing of de-identified data or publication of trial results.

Implementation of psychological clinical trials in epilepsy: Review and guide.

The International League Against Epilepsy (ILAE) Neuropsychiatry commission and United States Institute of Medicine report both identified cognitive and psychological comorbidities as a significant issue for individuals with epilepsy, with rates as high as 60%. However, there is a paucity of evidence-based treatments for many psychological conditions (e.g., learning disorders, cognitive disorders, behavioral disorders). Because of inherent challenges in the implementation of psychological therapy trials and specific considerations for the population with epilepsy, the focus of the current review was to provide guidance and recommendations to conduct psychological trials for individuals with epilepsy. Several key areas will be discussed, including selection of patients, trial design, psychological intervention considerations, outcomes and evaluation of results, publication of trial results, and special issues related to pediatric clinical trials. Rigorously designed psychological therapy trials will set the stage for evidence-based practice in the care of individuals with epilepsy, with the goal of improving seizures, side effects, and HRQOL.

P3.07-018 New European Clinical Trial Regulation: What's Going On?: Topic: Other – Geographical Differences

In the last decade Europe has faced a sharp slowdown in Clinical Research (CR) mainly due to European Directive 2001/20/CE application. Consequently the European Commission enacted the EU Regulation 536/2014 (ER) that is expected to become effective only in 2018, due to delays in the portal development. To investigate the ER perception and knowledge of the Italian professionals, two online surveys, addressed to Clinical Research Coordinators (CRCs) and Clinical Investigators (CIs), were conducted. Two anonymous web-based surveys, both consisting of 17 questions, have been used. The 62.5% and 58.9% of the contacted CIs and CRCs respectively answered to the survey: 12% of the CIs have a fully knowledge of the incoming ER while many are only partially (64%) or not (24%) informed. 80.4% of CRCs demonstrate a complete knowledge and are already trained. Amongst the evaluated topics, the need of a Reporting Member State in the first stage of the evaluation process is considered as positive by 74% of the CIs and almost all (90%) believe that this procedure will reduce the approval time. With regards to newly imposed transparency standards, 86% of the CIs would welcome the publication of trial results, while 14% believes that this obligation should only apply to profit trials. Overall 70% of CIs state that staff site’s facilities already met all of the ER imposed qualification. The 50% of CIs foresee that the ER will promote independent CR while 42% supposes that it will essentially affect the profit trials. Even though 71.4% of CRCs do not have a definite opinion on ER, 85.7% is convinced that it will have a direct impact on their job. The ER is a turning point for European CR: it is designed to ensure faster procedures, with positive effects both on timing and overall costs and it will require a rigorous methodology and an increased quality. The surveys highlighted different opinions among CIs and CRCs on Italian ability to rise to this challenge: while CIs believe that the centers already met the imposed requirements with only an initial period of transition, CRCs are less optimistic and report fails of their management to engage plans to be ready to the ECTR adoption. This process will involve big efforts and resources, but the payback is the opportunity to be on board of innovative treatments for the Italian patients.

Gestational Age Assessment in the Ghana Randomized Air Pollution and Health Study (GRAPHS): Ultrasound Capacity Building, Fetal Biometry Protocol Development, and Ongoing Quality Control

BackgroundFour million premature deaths occur yearly as a result of smoke from cooking fires. The Ghana Randomized Air Pollution and Health Study (GRAPHS) is underway in the Kintampo North municipality and South district of rural Ghana to evaluate the impact of improved cook stoves introduced during pregnancy on birth weight and childhood pneumonia. These hypotheses are being tested in a cluster-randomized intervention trial among 1415 maternal-infant pairs within 35 communities assigned to a control arm (traditional cooking) or one of two intervention arms (cooking with an improved biomass stove; cooking with liquefied petroleum gas stoves).ObjectiveThe trial is designed to ensure delivery of the stove intervention prior to the period of maximal fetal growth. To answer questions about the impact of household air pollution on pregnancy outcome, accurate gestational age assessment is critical. This manuscript describes in detail the development of the gestational dating protocol, intensive ultrasound training involved, ultrasound capacity building, and ultrasound quality control program.MethodsUltrasound training occurred in several phases over the course of 2 years. Training included a basic obstetric ultrasound course offered to all midwives performing antenatal care at the two study hospitals, followed by a more intense period of hands-on training focused on fetal biometry for a select group of providers demonstrating aptitude in the basic course. A standard operating procedure was developed describing how to obtain all fetal biometric measurements. Consensus was obtained on how biometric images are used in the trial to establish gestational age and estimate the delivery date. An ongoing ultrasound quality control program including the use of an image scorecard was also designed.ResultsPublication of trial results is anticipated in late 2016.ConclusionsUse of ultrasound should be strongly considered in field-based trials involving pregnant women to accurately establish gestational age, as menstrual dates may be incorrect or unknown. The inclusion of ultrasound in areas where ultrasound capacity does not previously exist requires a significant investment of time and resources. Such investment ensures appropriate training, high quality images, and accurate dating pregnancies. We outline our ultrasound training, image acquisition, quality control, and dating protocols in detail.Trial RegistrationClinicaltrials.gov NCT01335490; http://clinicaltrials.gov/ct2/show/NCT01335490 (Archived by WebCite at http://www.webcitation.org/6UbERJNO6).

Clinicopathological and prognostic significance of HER2 overexpression in gastric cancer: a meta-analysis of the literature

Human epidermal growth factor receptor 2 (HER2) plays an important role in the aggressiveness and progression of gastric cancer. With the publication of trial results, we conducted a meta-analysis to investigate its prognostic significance for patients with gastric cancer. PubMed, Ovid, Web of Science, and Cochrane databases were searched. Statistical analysis was carried out by STATA version 12.0 software. The Newcastle-Ottawa scale was used to assess the quality of evidence. Fifteen studies involving 5,290 patients met the inclusion criteria. The results showed that HER2 overexpression was significantly associated with patients' overall survival (HR = 1.56, 95% confidence interval (CI) 1.05-2.07; Z = 6.03; P = 0.000). The results also suggested that HER2 overexpression was associated with Bormann type (odds ratio (OR) = 1.76, 95% CI 1.19-2.59; Z = 2.85; P = 0.004), tumor differentiation (OR = 3.14, 95% CI 1.91-5.17; Z = 4.49; P = 0.000), Lauren's classification (OR = 6.25, 95% CI 4.29-9.10; Z = 9.54; P = 0.000), lymph node metastasis (OR = 1.43, 95% CI 1.15-1.77; Z = 3.23; P = 0.001), venous invasion (OR = 1.69, 95% CI 1.15-2.48; Z = 2.67; P = 0.008), and lymphovascular invasion (OR = 1.57, 95% CI 1.21-2.04; Z = 3.4; P = 0.001). However, it had no correlation with tumor size, depth of invasion, and tumor stage. This study showed that HER2 overexpression had an unfavorable prognostic role for patients with gastric cancer. HER2-positive expression was associated with Bormann type, Lauren's classification, tumor differentiation, lymph node status, venous invasion, and lymphovascular invasion.

A Systematic Review Of All Interventional Sickle Cell Trials Registered At Clinicaltrials.Gov

BackgroundClinicaltrials.gov was created in 2000 to comply with the FDA Modernization Act of 1997 and since 2007, Federal law (Section 801 of the FDA Amendments Acts) mandates registration of all applicable, prospective clinical drug trials of health outcomes. ICMJE journals also require registration of all intervention trials prior to publication. Clinicaltrials.gov offers patients and clinicians a valuable tool to identify open sickle cell disease (SCD) clinical trials by disease and results of closed trials with links to manuscripts. ObjectiveTo conduct a systematic review of all completed interventional SCD trials registered at clinicaltrials.gov and identify enrollment rates and reporting of trial results. MethodsWe performed a search of “sickle” in www.clinicaltrials.gov to identify every registered SCD clinical trial. (Last update: August 5, 2013). Every “closed” “interventional” registered trial was recorded in a database to include: trial name, trial identifier, start/stop date, sponsor/collaborator, primary objectives, enrollment age, expected enrollment, type of trial, and manuscripts. For trials without a manuscript in the registry, we performed a Pubmed search by keywords from the trial title, intervention, and/or PI. All manuscripts identified were reviewed to confirm trial enrollment numbers. ResultsThree hundred and fifty three SCD trials were registered, of which 212 (60%) were closed or completed. We performed a systematic review of 147 “interventional”, closed trials. (1983-2012). The primary sponsor or collaborator listed for these trials included an academic center (n=72, 41 unique centers registered trials), industry or pharmaceutical company (n=47), and/or NIH (n=45). Ninety trials (61%) were registered as either phase I or II, 29 (20%) registered as phase III, 8 (5%) registered as phase 4, and 20 trials did not provide a phase. Fifty two percent of trials were randomized. For trials that listed inclusion criteria for age, 41% were pediatric trials, 50% were adult, and 9% were both pediatric and adult. The most frequent outcomes of interest for these trials were pain (22%), bone marrow transplant (12%), pulmonary hypertension (7.5%), and endothelial function/dysfunction (5.5%).The reporting of trial results and manuscripts to clinicaltrials.gov was low. Nineteen of 147 (13%) trials completed the “trial results” section in clinicaltrials.gov. Twenty six trials downloaded their primary manuscript to clinicaltrials.gov despite 51 trials having manuscripts published on Pubmed. Eighty seven closed clinical trials registered on clinicaltrials.gov have not reported their trial results to clinicaltrials.gov or published their manuscripts as searched in Pubmed.Barriers to successful enrollment in SCD trials were evident in this review. Thirty two (22%) trials updated their registry to reflect “study termination” or “withdrawal”. For the 27 trials that listed the reason for this early termination/withdrawal, 17 (63%) were closed for slow enrollment. Barriers to enrollment in phase III trials were identified as 45% of phase III trials enrolled < 60% of their expected participants. The reporting of phase III trials was also low as only 16 (55%) of the registered phase III trials results have published manuscripts. ConclusionClinicaltrials.gov can be a valuable tool for clinicians to identify SCD clinical trials, but in practice is limited by investigator reporting of trial results. SCD clinical trials that are under-enrolled or not published place subjects at risk for participation in a trial without a scientific benefit to their disease community. Research should continue to focus on identifying and overcoming barriers to enrollment in clinical trials and publication of trial results. Disclosures:No relevant conflicts of interest to declare.

Potential implications of wider data transparency in medical communications

The current medical communication environment is characterised by growing calls for increased data transparency. There are ongoing concerns about the selective publication of trial results and the potential impact on use of medicines by prescribers and patients in both Europe and the US. This article outlines some of the background to current developments and considers the potential impact on those working in the field of medical communications.

Clinical trials in cardiovascular medicine.

The practice of cardiology is increasingly driven by evidence-based medicine centering around the results of clinical trials.1 In this inaugural article of Clinical Cardiology: Physician Update , I will focus on the design, analysis, and interpretation of clinical trials in cardiovascular medicine. Armed with the tools described herein, clinicians will be better equipped to understand and synthesize the results of the multitude of clinical trials appearing in the cardiology literature. A major goal of this effort is to shorten the delay between the publication of trial results and the translation of their findings into clinical practice. Trials of new therapies in cardiology typically compare the new treatment to a control. The control group receives the treatment against which the test intervention is being compared. Control and test treatments must be both medically justifiable and compatible with the healthcare needs of study patients. Either treatment must be acceptable to study patients and to the physicians administering them; there must be a reasonable doubt regarding the efficacy of the test treatment; and there should be reason to believe that the benefits will outweigh the risks of treatment. When the control treatment is a placebo, the trial is referred to as a placebo-controlled trial.2 Given the burgeoning supply of new treatments in the cardiovascular armamentarium, more and more trials compare the test therapy to a standard therapy. This is referred to as an active controlled trial.3 4 Randomized controlled trials typically involve the randomization of patients to either the control or test treatment (ie, randomized concurrent control). These trials are the gold standard for evaluating new therapies, and they form the foundation for the highest level of recommendations in practice guideline documents that stress evidence-based medicine5 (Figure 1⇓). Randomization has 3 important influences that explain why it is …

Operational aspects of terminating randomization in the multicenter trial of cryotherapy for retinopathy of prematurity

The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) is a randomized clinical trial sponsored by the National Eye Institute (NEI) designed to test whether cryotherapy applied to eyes of premature infants with a specified extent of stage 3+ ROP significantly decreases the incidence of an unfavorable outcome. An unfavorable outcome is defined as either retinal detachment or a retinal fold and was determined at 3 months posttreatment by the use of a masked photographic system. Enrollment into the trial was terminated on recommendation of the Data and Safety Monitoring Committee 9 months before the scheduled closing data for enrollment because of demonstrated treatment benefit. The purpose of this article is to discuss the operations involved in the orderly termination of enrollment and dissemination of results from this trial. These activities included preparation of trial participants and staff, release of trial information, continuing patient care, data collection and coding, and publication of trial results.