Early closure of clinical trials: The experience of the National Cancer Institute of Canada Clinical Trials Group

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6053-6053 ◽  
Author(s):  
W. Parulekar ◽  
J. L. Pater
Keyword(s):  
Clinical Trials ◽  
Meta Analysis ◽  
Phase Iii ◽  
External Information ◽  
Efficacy Analysis ◽  
Time Period ◽  
Number Of Patients ◽  
Early Closure ◽  
Phase Iii Studies ◽  
Over Time

6053 Background: Phase III studies require a significant commitment on behalf of researchers and patients. Closure of a study before the originally planned number of patients have been enrolled may be due to a number of reasons such as poor accrual, information within the study that precludes continuation such as excess toxicity, an interim futility or extreme efficacy analysis or data from outside sources that render the study question obsolete. Methods: We reviewed the phase III activity of our group since inception. Reasons for early closure were classified in the following manner: accrual failure (AF), external information (EI), internal information (II). Studies were grouped by site and time period of study activation to demonstrate any trends over time. Results: 94 phase III studies led by our group were identified from our roster. Reasons for early closure are presented below. Other sites include brain with an early closure due to AF, head/neck where 1 of 3 studies closed due to AF, melanoma where 1 of 3 studies closed due to EI and sarcoma where 2 studies were successfully completed. Several of the studies that closed for accrual failure were nevertheless published either singly or as part of a meta-analysis. Conclusions: Slightly over one third of studies closed prior to achievement of the targeted sample size. Accrual failure continues to be the main cause of early study closure (27/34 or 80%) with a trend towards decreasing frequency of occurrence over time. Emerging data within or external to a study leading to study closure are important but relatively rare reasons for early closure. [Table: see text] No significant financial relationships to disclose.

scholarly journals Bevacizumab and Breast Cancer: A Meta-Analysis of First-Line Phase III Studies and a Critical Reappraisal of Available Evidence

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
José R. Rossari ◽  
Otto Metzger-Filho ◽  
Marianne Paesmans ◽  
Kamal S. Saini ◽  
Alessandra Gennari ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fixed Effects ◽  
Meta Analysis ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Phase Iii ◽  
First Line ◽  
Statistical Estimates ◽  
Treatment Indications ◽  
Phase Iii Studies

Background. Randomized studies have shown different magnitude of bevacizumab benefit in the treatment of advanced breast cancer. Regulatory agencies have modified bevacizumab treatment indications across different regions. In this study, we perform a meta-analysis of phase III studies aiming to interrogate the magnitude of bevacizumab benefit for the treatment of first-line HER2-negative metastatic breast cancer (MBC).Methods. Data from studies E2100, AVADO and RIBBON-1 were used to calculate the benefit of bevacizumab in terms of tumor overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and toxicities. Combined statistical estimates of hazard ratios (HR) and odds ratios were calculated using fixed-effects or random-effects models.Results. A total of 2,695 patients were evaluated. Combining bevacizumab with different chemotherapy backbones resulted in a 30% risk reduction of PFS events (HR = 0.70; 95% confidence interval [CI], 0.57–0.86) and increased ORR (odds ratio 1.81; 95% CI, 1.53–2.14). No OS benefit could be demonstrated (HR = 0.95; 95% CI, 0.85–1.06). Bevacizumab significantly increased the incidence of adverse events such as proteinuria, hypertension and cardiovascular events.Conclusions. Bevacizumab combined with chemotherapy in the first-line treatment of MBC significantly improved ORR and PFS, but also increased grade 3-4 toxicities. No significant OS advantage was observed.

scholarly journals Surveillance in inflammatory bowel disease: is chromoendoscopy the only way to go? A systematic review and meta-analysis of randomized clinical trials

2020 ◽  
Vol 08 (05) ◽  
pp. E578-E590
Author(s):  
Ricardo Hannum Resende ◽  
Igor Braga Ribeiro ◽  
Diogo Turiani Hourneaux de Moura ◽  
Facundo Galetti ◽  
Rodrigo Silva de Paula Rocha ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Narrow Band ◽  
Narrow Band Imaging ◽  
Meta Analysis ◽  
Mean Difference ◽  
Procedure Time ◽  
High Definition ◽  
Number Of Patients

Abstract Background and study aims Ulcerative colitis (UC) and Crohn’s disease (CD) have higher risk of colorectal cancer (CRC). Guidelines recommend dysplasia surveillance with dye-spraying chromoendoscopy (DCE). The aim of this systematic review and meta-analysis was to review all randomized clinical trials (RCTs) available and compare the efficacy of different endoscopic methods of surveillance for dysplasia in patients with UC and CD. Methods Databases searched were Medline, EMBASE, Cochrane and SCIELO/LILACS. It was estimated the risk difference (RD) for dichotomous outcomes (number of patients diagnosed with one or more dysplastic lesions, total number of dysplastic lesions diagnosed and number of dysplastic lesions detected by targeted biopsies) and mean difference for continuous outcomes (procedure time). Results This study included 17 RCTs totaling 2,457 patients. There was superiority of DCE when compared to standard-definiton white light endoscopy (SD-WLE). When compared with high-definition (HD) WLE, no difference was observed in all outcomes (number of patients with dysplasia (RD 0.06; 95 % CI [–0.01, 0.13])). Comparing other techniques, no difference was observed between DCE and virtual chromoendoscopy (VCE – including narrow-band imaging [NBI], i-SCAN and flexible spectral imaging color enhancement), in all outcomes except procedure time (mean difference, 6.33 min; 95 % CI, 1.29, 11.33). DCE required a significantly longer procedure time compared with WLE (mean difference, 7.81 min; 95 % CI, 2.76, 12.86). Conclusions We found that dye-spraying chromoendoscopy detected more patients and dysplastic lesions than SD-WLE. Although no difference was observed between DCE and HD-WLE or narrow-band imaging, the main outcomes favored numerically dye-spraying chromoendoscopy, except procedure time. Regarding i-SCAN, FICE and auto-fluorescence imaging, there is still not enough evidence to support or not their recommendation.

scholarly journals Trends in clinical trials for stroke by cell therapy: data mining ClinicalTrials.gov and the ICTRP portal site

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Takaharu Negoro ◽  
Hanayuki Okura ◽  
Midori Maehata ◽  
Shigekazu Hayashi ◽  
Satoru Yoshida ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cell Therapy ◽  
Chronic Phase ◽  
Cell Types ◽  
Phase Iii ◽  
Definitive Treatment ◽  
Stroke Treatment ◽  
Portal Site ◽  
Therapy Studies ◽  
Phase Iii Studies

Abstract Definitive treatment of stroke constitutes an important thesis of regenerative medicine in the cerebrovascular field. However, to date, no cell therapy products for stroke are yet on the market. In this study, we examined the clinical research trends related to cell therapy products in the stroke field based on data obtained from the ClinicalTrials.gov website and International Clinical Trials Research Platform (ICTRP) portal site. These data do not offer results of clinical trials comprehensively but provide information regarding various attributes of planned clinical trials including work in progress. We selected 78 cell therapy studies related to the field of stroke treatment from ClinicalTrial.gov and ICTRP. These were analyzed according to, e.g., the reporting countries, origin (autologous or allogeneic), of cell used, cell types and source organs, the progress of translational phases, target phase of the disease (acute or chronic stroke), and route of administration. This analysis revealed a trend whereby in the acute phase, mesenchymal stem cells were administered intravenously at a relatively higher dose, whereas in the chronic phase a small number of cells were administered intracranially. Only two randomized controlled Phase III studies with over 100 patients are registered, but none of them has been completed. Thus, cell therapy against stroke appears to constitute a premature area compared with cartilage repair as assessed in our previous report. In addition, tracking by means of the ID number of each trial via PubMed revealed that 44% of clinical studies in this field have corresponding published results, which was also discussed.

Use of placebo in cancer medicine: The experience of a National Clinical Trials organization

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6104-6104
Author(s):  
J. L. Pater ◽  
W. Parulekar
Keyword(s):  
Clinical Trials ◽  
Supportive Care ◽  
Study Design ◽  
Standard Of Care ◽  
Phase Iii ◽  
Design Data ◽  
Standard Of Care Treatment ◽  
Prevention Trials ◽  
The Impact ◽  
Phase Iii Studies

6104 Background: The use of placebos in cancer clinical trials requires careful evaluation. Factors that must be considered include the impact of placebo on endpoint measurement, the efficacy of placebo relative to standard of care treatment, patient altruism/acceptance of a non-active intervention and the resulting increase in complexity of study conduct with respect to randomization, drug supply, data management, analysis and the unblinding process. Methods: We reviewed the experience of the National Cancer Institute of Canada Clinical Trials Group with the use of placebo in the randomized phase III setting from 1982–2005. Results: Since 1982, 34 studies were identified that utilized a placebo as part of study design. Data is presented below according to the type of study and date of study activation. The numbers in brackets represent those studies in which placebo was used alone in the control arm. Supportive care studies were the most common type of study employing a placebo as part of study design and constituted almost 50% of our Group’s experience. Therapeutic studies involving placebo were conducted in multiple sites including breast (4), lung (6), myeloma (1), melanoma (1), ovary (1) and pancreas (1). Conclusion: Phase III studies involving a placebo constitute an important part of our clinical trial activity and cross the spectrum of supportive care, therapeutic and prevention trials. The use of placebo in cancer studies may increase due to the relative ease of blinding in studies that evaluate targeted, oral therapies with minimal toxicities as well as the need for unbiased assessment of increasingly used endpoints such as time to progression. [Table: see text] No significant financial relationships to disclose.

Evolution of statistical methodology and design of phase II/III clinical trials in non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7108-7108 ◽  
Author(s):  
R. K. Bagai ◽  
A. Dowlati
Keyword(s):  
Clinical Trials ◽  
Survival Time ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Iii ◽  
Type I ◽  
Phase Ii Trials ◽  
Improvement In Survival ◽  
Phase Ii And Iii ◽  
Phase Iii Studies

7108 Background: A significant heterogeneity exists in the design and reporting of phase II and III therapeutic clinical trials in NSCLC. This has led to difficulty in interpretation of these trials leading to over- or underestimation of therapeutic efficacy. We set out to investigate the statistical methodology and design reporting of chemotherapeutic trials in NSCLC published in the Journal of Clinical Oncology (JCO) over 20 years. Methods: We identified all phase II and III NSCLC chemotherapy trials published in the JCO from January 1983 to August 2005. All manuscripts were reviewed to evaluate components of statistical design that were reported, including: sample size calculation, power, type I error, single or multiple drug trials, relative response sought in phase II trials and improvement in survival time or response rate sought in phase III trials. Results: One hundred forty eight trials were identified. 52% of studies were phase III and 48% were phase II. The majority (78%) were conducted in advanced stage NSCLC. Sample size calculations were reported for only 58% of phase III studies and 31% of phase II studies. Power was reported in 66% of phase III studies and 13% of phase II trials. Type I error was reported in 47% of phase III studies and 17% in phase II studies. 60% of phase III trials defined endpoints (percentage improvement in survival time, improvement in survival time in months or increase in response rate). 41% of phase II trails defined the target response rate, ranging from response rates of 15% to 70%. The frequency of adequate reporting of statistical design was shown to increase from 31% in 1990–1995 to 64% in 2000–2005 ( table ). Conclusions: Significant heterogeneity exists in trial design and reporting of phase II and III trials in NSCLC. This impacts the ability to adequately interpret these studies. More widespread application of statistical methods in planning and reporting of lung cancer clinical trials are necessary to increase reliability of data. [Table: see text] No significant financial relationships to disclose.

Prevalence and characteristics of prematurely terminated cancer clinical trials.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 6613-6613
Author(s):  
Kristian D Stensland ◽  
Asma Latif ◽  
Ryan Hendricks ◽  
Nitin Roper ◽  
Russell McBride ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Premature Termination ◽  
Disease Type ◽  
Phase Iii ◽  
Financial Resources ◽  
Cancer Clinical Trials ◽  
Enrollment Status ◽  
Substantial Investment ◽  
Early Closure ◽  
Study Sites

6613 Background: Cancer clinical trials require a substantial investment of patient and financial resources. Trials that are terminated prematurely contribute little to the scientific knowledge base and divert resources from answering other critical questions. To our knowledge, the prevalence of prematurely terminated trials, and reasons for termination, has not been comprehensively assessed. Methods: The ClinicalTrials.gov database was queried to identify all phase II and phase III interventional trials for any neoplasm registered between 9/2005 and 11/2012. The disease type, enrollment status, phase, funding source, and number of study sites were collected for each trial. A ”prematurely terminated” trial was any trial with a status of “terminated,” “withdrawn,” or “suspended.” The reason for termination was collected for each prematurely terminated trial. Results: We identified 11,483 interventional cancer trials, of which 1,326 (11.5%) were terminated prematurely. The reasons for termination are shown in the Table. The proportion of cancelled trials was similar among the various disease types, but was slightly higher in lung cancer (14.4% vs. 11.2%, p = 0.001), and slightly lower in skin cancer (8.2% vs. 11.7%, p = 0.022). The most common reason for premature termination was poor accrual (33.1%) though no reason was provided for 23% of trials. Trials sponsored by industry were more likely to be canceled than those with NIH or “other” sponsorship (13.4% vs. 9.9%, p = 0.001). Single center trials were more likely to be canceled than trials with multiple sites (13.6% vs. 9.4%, p < 0.001). Conclusions: More than one in ten cancer clinical trials is terminated prematurely. Full reporting of the reasons for premature termination is necessary for further evaluation of the cancer clinical trial enterprise and identification of predictors of study early closure. [Table: see text]

Reno-vascular toxicities associated with carfilzomib: Systematic review and meta-analysis.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21622-e21622
Author(s):  
Chintan Shah ◽  
Harini Bejjanki ◽  
Rohit Bishnoi ◽  
Ankur Jain ◽  
Subhankar Samal ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Phase I ◽  
Meta Analysis ◽  
Random Effect ◽  
Random Effect Model ◽  
Dose Effect ◽  
Phase Iii ◽  
Control Group ◽  
Phase Iii Clinical Trials

e21622 Background: Carfilzomib (Carf) is a novel proteasome inhibitor that is approved for patients with relapsed multiple myeloma (RMM) who have failed ≥ 1 prior lines of therapy. The incidence and seriousness of Carf associated reno-vascular toxicities (RVT) is not well known. We performed systematic review of Carf literature with meta-analysis to determine its incidence and overall risk. Methods: Initial search of literature led to a total of 175 Carf related articles. However, we used a total of 29 publications; phase I/II, phase II and phase III clinical trials (n = 3) which used Carf as monotherapy or in combination. We excluded phase I studies. Incidence rates and odds ratios (OR) were calculated with either fixed effect or random effect model based on the heterogeneity of included studies. Toxicity such as hypertension (HTN), renal failure (RF) and venous thromboembolism (VTE) were reported according to CTCAE v4.0. Results: A total of 4560 patients with various hematological and solid malignancies were included. Incidences of toxicities were: 15.9% and 4.7 % for HTN, 11.2% and 3.44% for RF, 6.47% and 2.22% for VTE, respectively for all grades and high grades in each category. When compared to control group taken from phase III clinical trials, the risk of HTN and RF due to Carf was significantly higher [OR = 2.91 and 3.32 in HTN (P < 0.001)], [OR = 1.71 and 1.79 (P < 0.05) for RF], respectively for all grade and high grade in each category. Moreover, incidence of HTN with higher than standard dose of carf (27 mg/m2 twice weekly) was significantly higher (P < 0.001). RF and VTE did not have the dose effect. Concomitant use of immunomodulator (IMiD) significantly increased, as expected, the incidence of VTE (P < 0.001). There was no variation in the incidence of RVT among newly diagnosed versus RMM (P = 0.4). Conclusions: Overall incidence and risk of hypertension and renal toxicities seems to be high when using Carf. Higher doses of Carf seem to lead to higher incidence of HTN, while the risk of VTE is higher with concomitant IMiD use. The pathophysiology for these complications is poorly understood, however it could be secondary to endothelial effect of carf. Physician should be vigilant about these effects as it can lead to poor overall outcomes.

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