Publication Of Clinical Trial Results Research Articles

Advancing Patient Care in the Evolving Prostate Cancer Treatment Landscape

Most prostate cancer cases present as localised disease at initial diagnosis but can progress in about a fifth of patients to castration-resistant prostate cancer (CRPC) within 5 years. A major concern for patients and physicians is the development of metastases, affecting quality of life (QoL), and reducing overall survival (OS). Treatment guidelines for the different stages of prostate cancer continue to be modified with the publication of clinical trial results. Currently, androgen receptor inhibitors (ARi) are used in the management of non-metastatic CRPC. Among these, explained Martin Bögemann, Department of Urology, University of Münster, Germany, darolutamide’s unique structure means it causes minimal side effects, likely due to reduced blood-brain barrier penetration, while also reducing the potential for drug-drug interactions, which is especially important for patients treated for comorbidities. Treatment of metastatic hormone-sensitive prostate cancer (mHSPC) depends on a variety of factors, including when metastases developed in the course of disease and their volume. Bertrand Tombal, Institute of Experimental and Clinical Research, Université Catholique de Louvain, Belgium, described the evolution of mHSPC therapy from androgen deprivation therapy (ADT) and surgical castration as the only available options, to the emergence of the chemotherapeutic docetaxel and androgen receptor pathway inhibition (ARPI). He explained the results of Phase III clinical trials of various combination approaches, with a combination treatment of docetaxel, ADT, and darolutamide showing promise for overall survival. Discussions are ongoing about which patients with mHSPC should receive this triple therapy approach. Christian Gratzke, Department of Urology, University Hospital Freiburg, Germany followed by describing how treatment decisions are made, including the role of imaging, with a case study of a patient with non-metastatic castration-resistant prostate cancer (nmCRPC), and another with mHSPC. A further panel discussion considered treatment options for various presentations of prostate cancer, and why one would be chosen over another. The panel concluded with a question and answer sessions that focused on when and why patients with prostate cancer are sent for genetic testing.

Results dissemination from completed clinical trials conducted at German university medical centers remained delayed and incomplete. The 2014 –2017 cohort

ObjectiveTimely publication of clinical trial results is central for evidence-based medicine. In this follow-up study we benchmark the performance of German university medical centers (UMCs) regarding timely dissemination of clinical trial results in recent years. MethodsFollowing the same search and tracking methods used in our previous study for the years 2009 – 2013, we identified trials led by German UMCs completed between 2014 and 2017 and tracked results dissemination for the identified trials. ResultsWe identified 1,658 trials in the 2014 –2017 cohort. Of these trials, 43% published results as either journal publication or summary results within 24 months after completion date, which is an improvement of 3.8% percentage points compared to the previous study. At the UMC level, the proportion published after 24 months ranged from 14% to 71%. Five years after completion, 30% of the trials still remained unpublished. ConclusionDespite minor improvements compared to the previously investigated cohort, the proportion of timely reported trials led by German UMCs remains low. German UMCs should take further steps to improve the proportion of timely reported trials.

Changes in Drug Utilization After Publication of Clinical Trials and Drug-Related Scandals in Japan: An Interrupted Time Series Analysis, 2005-2017.

BackgroundBreaches of ethics undermine the practice of medicine. In Japan, two major scandals involving clinical research and drug marketing occurred after the publication of clinical trials. To study the effects of those scandals, we evaluated changes in the use of first-generation angiotensin II receptor blockers (ARBs) after publication of relevant clinical trials and also after the subsequent scandals.MethodsWe conducted a quasi-experimental design of an interrupted time series analysis (ITSA) on nationwide monthly drug-market data covering 12 years (2005 to 2017) in Japan. The main outcome was the use of first-generation ARBs (valsartan, candesartan, and losartan). The two exposures were the publication of ARB-related clinical-trial results (October 2006) and subsequent ARB-related scandals involving research and marketing (February 2013). A generalized estimating equation model was fitted for ITSA with a log link, Poisson distribution, robust variance estimators, and seasonality adjustment.ResultsThe publication of clinical trials was associated with 12% increase in the use of first-generation ARBs in Japan, and the subsequent ARB-related scandals was associated with 19% decrease. The decrease in the use of first-generation ARBs after the scandals was greater than the increase in their use after the publication of clinical-trial results. The net effect of the two exposures was a 9% decrease in the use of first-generation ARBs.ConclusionsThe scandals were associated with decrease in the use of first-generation ARBs, and that decrease was greater than the increase associated with the publication of “successful” clinical trials, making the net effect not zero but negative.

Timing of US Food and Drug Administration (FDA) cancer drug approvals relative to publication of clinical trial results.

2071 Background: Publication of clinical trial results in peer reviewed literature is essential to inform clinicians regarding the use of new anti-cancer treatments, which often have a low therapeutic ratio and require careful assessment of risks and benefits. Publication of registration trials should precede FDA approval to facilitate evaluation and implementation of new therapies. The timing of trial publication relative to FDA drug approvals has not been systematically investigated. Methods: We collected all FDA drug approvals for a cancer indication between 2000-19. Trials were identified using FDA labels as well as drugs and publications indexed on HemOnc.org. Approvals for generics/biosimilars, non-oncology indications and label revisions without supportive evidence were excluded. Dates of approval, the approval pathway, approval type (new vs expansion), and the first full publication related to the registration were recorded. Trials and approvals were matched using available metadata. We calculated the proportion of drugs approved prior to publication overall and for those receiving accelerated approval (AA). We used logistic regression to compare rates of pre-publication approval by approval pathway and by new vs expanded approval. Results: Among a total of 378 drug approvals, 139 (37%) had pre-publication approval. Of these, the median overall time from approval to publication was 140 days (IQR 64-281 days). For those with approval after publication, median time from publication to approval was 157 days (IQR 72-359 days). The number of drugs approved pre-publication rose by 27% between the first and last quarters of the study period, though, the proportion decreased as more anti-cancer drugs have been approved in recent years (Table). More drugs were approved pre-publication through AA than regular approval (46% vs 34%, OR 1.66 [95% CI 1.03-2.70], p=0.04) and as new approvals vs. expanded approvals (45% vs 32%, OR 1.76 [95% CI 1.15-2.70], p=0.01). Conclusions: A substantial minority of FDA approvals occur before trial results are published, with the odds being higher for drugs receiving AA and for new approvals. Since clinicians rely upon published results to inform risk/benefit decisions, efforts are needed to ensure trial results are published by the time of FDA approval of new cancer drugs and indications. [Table: see text]

Clinical observation and management of COVID-19 patients

ABSTRACT Three leading infectious disease experts in China were invited to share their bedside observations in the management of COVID-19 patients. Professor Taisheng Li was sent to Wuhan to provide frontline medical care. He depicts the clinical course of SARS-CoV-2 infection. Furthermore, he observes the significant abnormality of coagulation function and proposes that the early intravenous immunoglobulin and low molecular weight heparin anticoagulation therapy are very important. Professor Hongzhou Lu, a leader in China to try various anti-viral drugs, expresses concern on the quality of the ongoing clinical trials as most trials are small in scale and repetitive in nature, and emphasizes the importance of the quick publication of clinical trial results. Regarding the traditional Chinese medicine, Professor Lu suggests to develop a creative evaluation system because of the complicated chemical compositions. Professor Wenhong Zhang is responsible for Shanghai's overall clinical management of the COVID-19 cases. He introduces the team approach to manage COVID-19 patients. For severe or critically ill patients, in addition to the respiratory supportive treatment, timely multiorgan evaluation and treatment is very crucial. The medical decisions and interventions are carefully tailored to the unique characteristics of each patient.

Responsible Translation of Stem Cell Research: An Assessment of Clinical Trial Registration and Publications.

SummaryWe assessed the extent to which the publication of clinical trial results of innovative cell-based interventions reflects International Society for Stem Cell Research best practice guidelines. We assessed: (1) characteristics and time to publication of completed trials; (2) quality of reported trials; and (3) results of published trials. We identified and analyzed publications from 1,052 novel stem cell clinical trials: 179 (45.4%) of 393 completed trials had published results; 48 trials were registered by known stem cell tourism clinics, none of which reported results. Completed non-industry-sponsored trials initially published more rapidly, but differences with industry-sponsored trials decreased over time. Most publications reported safety, and 67.3% (mainly early-stage trials) reported positive outcomes. A higher proportion of industry trials reported positive efficacy. Heightened patient expectations for stem cell therapies give rise to ethical obligations for the transparent conduct of clinical trials. Reporting guidelines need to be developed that are specific to early-phase clinical trials.

The significance of the trial outcome was associated with publication rate and time to publication

ObjectivesThis study aims to comprehensively assess the publication of clinical trial results and factors associated with their publication. Study Design and SettingPhase II and III trials of advanced breast cancer registered on ClinicalTrials.gov between October 1, 2000, and September 30, 2012, were identified. Publications were searched by using PubMed and reviewing those listed on the registry site. The main outcomes were publication rate, public availability of results, and time to publication. ResultsOf 352 phase II and 74 phase III trials, 12.5% and 31.1% were published, whereas 46.9% and 58.1% had publicly available results, respectively. Compared to those with significant results, studies with nonsignificant results had delays in time to publication (P < 0.001). Even after adjusting for funding source and phase type, the significance of study outcomes was a significant factor that affected time to publication (hazard ratio = 6.02; 95% confidence interval: 3.59, 10.07; P < 0.001), with trials with significant outcomes taking less time to publish than those with nonsignificant outcomes. ConclusionUnderreporting of results and nonpublication or delays in the publication of negative results were identified in registered trials of advanced breast cancer. Thus, further initiatives appear necessary to urgently address such publication bias.

Publication and Interpretation of Clinical Trial Results: The Need for Caution

When the results of a clinical trial are published, modern information technology ensures that news of the trial outcome is disseminated rapidly to the medical community worldwide, and often to the general public as well, through the media. However, there is always a danger that physicians, patients, and the general public may be inappropriately influenced by the ‘‘spin’’ that is put on what they read or hear, without subjecting the trial report to critical evaluation. The adverse and inappropriate effects that the publication of clinical trial results can have on medical practice were discussed in an editorial by Kaplan, who pointed out the heavy responsibilities that fall on the shoulders of reviewers and journal editors to ensure that trials do not have serious design flaws and that their results are clearly and accurately reported. The publication in February 2011 of the results of a large, randomized study assessing the value of completion lymph node dissection (CLND) in sentinel node (SN)positive breast cancer patients illustrates how problems of misinterpretation can arise. The trial report was published in the Journal of the American Medical Association (JAMA), a leading international medical journal, and it was featured on the front page of the New York Times shortly afterwards. The title of the report in JAMA was ‘‘Axillary dissection versus no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial.’’ However, the dramatic headline in the New York Times read, ‘‘Lymph node study shakes pillar of breast cancer care,’’ and there were similar alarmist headlines in other major newspapers around the world. As a result of this widespread press publicity, we have encountered patients with melanoma who are not willing to consider entry into another large clinical trial, this one assessing the value of CLND when metastatic melanoma has been found in a SN (MSLT-II—Clinicaltrials.gov identifier NCT00297895). These patients have become aware that in the trial report in JAMA, Giuliano and colleagues concluded that CLND is not necessary for breast cancer patients found to be SN-positive. The patients assume that the situation for SN-positive melanoma patients will be the same, not understanding that the two tumor types behave in quite different ways, and that in any case all the SN-positive patients with breast cancer enrolled in the trial received radiation therapy to the axilla, and most (96.5 %) also received systemic chemotherapy (known to be effective for breast cancer, but not for melanoma). Another trial, published in a major medical journal in November 2009, also is having a major impact on clinical trial accrual in patients with metastatic melanoma, in this case those with cerebral metastases. The trial was reported by Chang and colleagues in Lancet Oncology and will be referred to hereafter as the Chang trial. It studied patients with cerebral metastases from cancers of various types who were treated with stereotactic radiosurgery (SRS) with or without whole brain radiotherapy (WBRT). The Chang trial was stopped early because one of six neurocognitive function assessment tools showed a detrimental result at 4 months. It is unknown whether this was a temporary or permanent effect of WBRT, because the trial was terminated before sufficient follow-up times had been achieved to assess long-term results. There are many potential pitfalls in the design, conduct, and reporting of clinical trials, and the Chang trial appears to have had several flaws. Some of these have been detailed in published correspondence, but there are a Society of Surgical Oncology 2012

Uniform Clinical Trial Registration Policy for Journals of Kidney Diseases, Dialysis, and Transplantation

Medical research can be seriously compromised by the selective publication of clinical trial results. Therefore, it is imperative that information regarding clinical trials be available to the general public. We require, as a condition of consideration for publication, registration in a public

Changes in the use of postmenopausal hormone therapy after the publication of clinical trial results.

The recent publication of clinical trial results has led to a dramatic shift in the evidence about postmenopausal hormone therapy. To examine whether the publication of clinical trial results, specifically the Heart and Estrogen/progestin Replacement Study (HERS) in 1998 and the Women's Health Initiative (WHI) in 2002, has influenced the use of hormone therapy among postmenopausal women. Observational cohort (1997 to 2003). San Francisco Mammography Registry, San Francisco, California. Postmenopausal women between the ages of 50 and 74 years without a personal history of breast cancer who underwent mammography (151862 mammograms). Self-reported current use of hormone therapy. Among menopausal women who had mammography, it was estimated that 41% were currently using hormone therapy in 1997. Before the publication of HERS, the use of hormone therapy was increasing at a rate of 1% (95% CI, 0% to 2%) per quarter. After the publication of HERS, use decreased by 1% (CI, -3% to 0%) per quarter. In contrast, the publication of the WHI in 2002 was associated with a more substantial decline in the use of hormone therapy of 18% (CI, -21% to -16%) per quarter. Similar associations were observed for most subgroups of women, including women older than 65 years of age; women with a previous hysterectomy; and women who described their race or ethnicity as white, African American, Latina, Chinese, or Filipina. The release of the HERS data was temporally associated with a modest decline in the use of hormone therapy. In contrast, the release of the principal findings from the WHI was associated with a more substantial decline in use by postmenopausal women. The reason for the differences in decline may relate to the fact that the WHI results were widely publicized or were more applicable to most postmenopausal women because the WHI study was performed in healthy women.