A sense of urgency: Evaluating the link between clinical trial development time and the accrual performance of CTEP-sponsored studies

2009 ◽  
Vol 27 (18_suppl) ◽  
pp. CRA6509-CRA6509 ◽  
Author(s):  
S. Cheng ◽  
M. Dietrich ◽  
S. Finnigan ◽  
A. Sandler ◽  
J. Crites ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Odds Ratio ◽  
Development Time ◽  
Phase Iii ◽  
Multivariable Logistic Regression Analysis ◽  
Study Phase ◽  
Calendar Time ◽  
Activation Barriers ◽  
Oncology Clinical Trials ◽  
Phase Iii Trials

CRA6509 Background: Post-activation barriers to oncology clinical trial accruals are well documented; however, potential barriers prior to trial opening are not. We investigate one such barrier: trial development time. Methods: National Cancer Institute Cancer Therapy Evaluation Program (NCI-CTEP) sponsored trials for all therapeutic, non-pediatric phase I,I/II, II, and III studies activated in an eight year period (2000–2007) were investigated (n=553). Successful trials were those achieving 100% of minimum accrual goal. Time to open a study was the calendar time from initial CTEP submission to trialactivation. Multivariable logistic regression analysis was used tocalculate unadjusted and adjusted odds ratios, controlling for study phase and size of expected accruals. Results: 40.0 percent (n=221) of CTEP-approved oncology trials failed to achieve minimum accrual goals, with 49.2 percent (n=30) of phase III trials failing to achieve at least 25 percent of accrual goals. A total of 8,723 patients (17.0% of accruals) accrued to those studies that were unable to achieve the projected minimum accrual goal. Trials requiring 9–12 months development were significantly more likely to achieve accrual goals (odds ratio, 1.94; 95% CI, 1.06 to 3.52, P=0.031) than trials requiring the median time (15–18 months); trials that exceeded 27 months of development time were significantly less likely of achieving accrual goals (odds ratio, 0.14; 95% CI, 0.04 to 0.54, P=0.004). Conclusions: A large percentage of oncology clinical trials do not achieve minimum projected accruals. Trial development time appears to be one important predictor of the likelihood of successfully achieving the minimum accrual goals. [Table: see text] No significant financial relationships to disclose.

scholarly journals A Review of Phase III Clinical Trials of Prostate Cancer Chemoprevention

2007 ◽  
Vol 89 (3) ◽  
pp. 207-211 ◽  
Author(s):  
JF Thorpe ◽  
S Jain ◽  
TH Marczylo ◽  
AJ Gescher ◽  
WP Steward ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Cancer Prevention ◽  
Age Of Onset ◽  
Cancer Chemoprevention ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Prostate Cancer Prevention ◽  
Phase Iii Trials

INTRODUCTION Prostate cancer is an excellent target for chemoprevention strategies; given its late age of onset, any delay in carcinogenesis would lead to a reduction in its incidence. This article reviews all the completed and on-going phase III trials in prostate cancer chemoprevention. PATIENTS AND METHODS All phase III trials of prostate cancer chemoprevention were identified within a Medline search using the keywords ‘clinical trial, prostate cancer, chemoprevention’. RESULTS In 2003, the Prostate Cancer Prevention Trial (PCPT) became the first phase III clinical trial of prostate cancer prevention. This landmark study was terminated early due to the 24.8% reduction of prostate cancer prevalence over a 7-year period in those men taking the 5α-reductase inhibitor, finasteride. This article reviews the PCPT and the interpretation of the excess high-grade prostate cancer (HGPC) cases in the finasteride group. The lack of relationship between cumulative dose and the HGPC cases, and the possible sampling error of biopsies due to gland volume reduction in the finasteride group refutes the suggestion that this is a genuine increase in HGPC cases. The other on-going phase III clinical trials of prostate cancer chemoprevention – the REDUCE study using dutasteride, and the SELECT study using vitamin E and selenium – are also reviewed. CONCLUSIONS At present, finasteride remains the only intervention shown in long-term prospective phase III clinical trials to reduce the incidence of prostate cancer. Until we have the results of trials using alternative agents including the on-going REDUCE and SELECT trials, the advice given to men interested in prostate cancer prevention must include discussion of the results of the PCPT. The increased rate of HGPC in the finasteride group continues to generate debate; however, finasteride may still be suitable for prostate cancer prevention, particularly in men with lower urinary tract symptoms.

scholarly journals Ethical guidelines for deliberately infecting volunteers with COVID-19

2020 ◽  
Vol 46 (8) ◽  
pp. 502-504 ◽  
Author(s):  
Adair D Richards
Keyword(s):  
Phase Ii ◽  
Development Time ◽  
Ethics Committees ◽  
Phase Iii ◽  
Ethical Standards ◽  
Ethical Guidelines ◽  
Phase Iii Trials

Global fatalities related to COVID-19 are expected to be high in 2020–2021. Developing and delivering a vaccine may be the most likely way to end the pandemic. If it were possible to shorten this development time by weeks or months, this may have a significant effect on reducing deaths. Phase II and phase III trials could take less long to conduct if they used human challenge methods—that is, deliberately infecting participants with COVID-19 following inoculation. This article analyses arguments for and against such methods and provides suggested broad guidelines for regulators, researchers and ethics committees when considering these matters. It concludes that it may be possible to maintain current ethical standards yet still permit human challenge trials in a context where delay is critical. The implications are that regulators and researchers need to work together now to design robust but short trials and streamline ethics approval processes so that they are in place when applications for trials are made.

Declared pharmaceutical industry involvement in a random sample of abstracts from the ASCO Annual Meetings

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e17525-e17525
Author(s):  
A. L. Masson ◽  
A. Mangabeira ◽  
E. D. Saad ◽  
F. E. Prisco
Keyword(s):  
Pharmaceutical Industry ◽  
Phase I ◽  
Phase Iii ◽  
Study Phase ◽  
Single Institution ◽  
Us Studies ◽  
Phase Ii Studies ◽  
Phase Iii Trials ◽  
Future Publication ◽  
Oral Presentations

e17525 Background: The pharmaceutical industry (PI) plays an important role in drug development. We examined the extent and correlates of declared PI involvement in abstracts presented at ASCO Meetings 2001–2003 and 2006–2008. Methods: After stratification of abstracts into three categories of presentation ([1] oral, including plenary and oral presentations, and integrated symposia; [2] poster, including poster discussion and general poster; and [3] publication only), we randomly selected 10% of the abstracts for each of the 3-year periods of interest. Involvement by the PI was defined as declared sponsorship or by co-authorship in abstracts. Multivariate analysis (MVA) was done using logistic regression. Results: In the 2,206 abstracts analyzed, there was declared sponsorship or co-authorship by the PI in 425 (19.3%) of cases. Declared sponsorship (N = 73) was less frequent than co-authorship (N = 364). Declared sponsorship or co-authorship was present in 160 of 332 (48.2%) multinational studies, 222 of 969 (22.9%) multicenter, uninational studies, and 43 of 905 (4.3%) of single-institution studies (p < 0.001). For the 30.6% of abstracts stating the study phase in the title or text, PI involvement was present in 116 of 239 (48.5%) phase I studies, 95 of 364 (26.1%) phase II studies, and 26 of 72 (36.1%) phase III trials (p < 0.001). PI involvement was present in 280 of 1,080 (25.9%) US studies and in 145 of 1,126 (12.9%) non-US studies (p < 0.001). In MVA, significant predictors of PI involvement were multinationality (odds ratio [OR] = 6.61), phase I/II/III (versus other, OR = 3.65), and US nationality (OR = 2.98). Conclusions: Declared PI involvement is seen in nearly 20% of abstracts and is more frequent in multinational studies, clinical trials and studies with US nationality. Additional work is needed to assess the correlation between PI involvement, abstract quality and likelihood of future publication. No significant financial relationships to disclose.

scholarly journals ‘Optimism bias’ in contemporary national clinical trial network phase III trials: are we improving?

2018 ◽  
Vol 29 (10) ◽  
pp. 2135-2139 ◽  
Author(s):  
Kaveh Zakeri ◽  
Sonal Noticewala ◽  
Lucas Vitzthum ◽  
E. Sojourner ◽  
Hanjie Shen ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Iii ◽  
Optimism Bias ◽  
Trial Network ◽  
Clinical Trial Network ◽  
Phase Iii Trials

Role of Sensitivity Analyses in Assessing Progression-Free Survival in Late-Stage Oncology Trials

2009 ◽  
Vol 27 (35) ◽  
pp. 5958-5964 ◽  
Author(s):  
Suman Bhattacharya ◽  
Gwen Fyfe ◽  
Robert J. Gray ◽  
Daniel J. Sargent
Keyword(s):  
Clinical Trial ◽  
Late Stage ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Sensitivity Analyses ◽  
Potential Bias ◽  
Primary Analysis ◽  
Free Survival ◽  
End Point ◽  
Phase Iii Trials

Sensitivity analysis is an important statistical technique that assesses whether the results of phase III trials are robust and likely to be generalizable. Until recently, sensitivity analyses were rarely included in phase III trials, and they remain poorly understood by many oncologists. Sensitivity analyses are critical to understanding the strength of conclusions made in the primary analysis of a late-stage clinical trial. They examine the influence of protocol design errors, unintended biases, deviations from assumptions underlying statistical models, and any unanticipated treatment delivery or practice patterns on trial results. In trials with complex or subjective end points, they also allow an understanding of the extent to which a positive outcome is driven by a single, possibly subjective, and therefore biased, element of an end point. The purposes of this article are to explain how sensitivity analyses are performed, to discuss areas of a clinical trial where sensitivity analyses should focus, and to illuminate the importance of this technique in the rigorous evaluation of late-stage clinical trial data, using specific examples. This article focuses on late-stage trials that use progression-free survival or time to progression as their primary end point, because sensitivity analyses are particularly important in these cases for which the end point is potentially subject to bias. Three sources of potential bias are explored: assessment time, symptomatic (ie, nonradiologic) disease progression, and missing data. For each source of potential bias, case studies are presented to highlight the role that sensitivity analyses play in determining whether the trial's conclusions are robust.

scholarly journals Changing Perspectives in Diabetic Macular Oedema – Recognising and Understanding Chronic Diabetic Macular Oedema

2014 ◽  
Vol 08 (02) ◽  
pp. 145
Author(s):  
Usha Chakravarthy ◽  
Albert Augustin ◽  
Yit Yang ◽  
Michael Diestelhorst ◽  
Pascale Massin ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Macular Oedema ◽  
Diabetic Macular Oedema ◽  
Clinical Trial Data ◽  
Fluocinolone Acetonide ◽  
Phase Iii ◽  
Real World Data ◽  
First Line Therapy ◽  
Line Therapy ◽  
Phase Iii Trials

The satellite symposium moderated by Usha Chakravarthy entitled ‘Changing Perspectives in Diabetic Macular Oedema: Recognising and Understanding Chronic Diabetic Macular Oedema’ was convened at the 2014 EURETINA Congress. The symposium discussed the multiple processes involved in chronic diabetic macular oedema (DMO) and the use of medications, in particular, corticosteroids in its management. As DMO progresses, inflammatory cytokines are up-regulated relative to vascular endothelial growth factor (VEGF) and these promote various pathways that ultimately result in retinal damage in chronic disease. It is important therefore that treatments for chronic DMO address this altered inflammatory cytokine profile to effectively manage the condition. ILUVIEN®, a 190 μg intravitreal implant in applicator (with a daily release rate of 0.2 μg/day fluocinolone acetonide [FAc] implant) is a second-line therapy indicated for the treatment of chronic DMO. This implant has been shown in phase III trials to lead to marked improvements in visual acuity and in retinal thickness in patients with chronic DMO that were insufficiently response to first-line therapy (i.e. laser). Clinical trial data strongly support the use of the FAc implant in chronic DMO and now ‘real world’ data from its use in regular clinical practice are becoming available and interim results complement those reported in a clinical trial setting.

scholarly journals The Damaging Outcome of the POLAR Phase III Trials Was Due to Avoidable Time-Dependent Redox Interaction between Oxaliplatin and PledOx

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1937
Author(s):  
Jan Olof G. Karlsson ◽  
Per Jynge ◽  
Louis J. Ignarro
Keyword(s):  
Clinical Trial ◽  
Phase Iii ◽  
Polar Phase ◽  
Negative Results ◽  
M Phase ◽  
Phase Iii Trials ◽  
Modified Folfox6 ◽  
Redox Interaction ◽  
Administration Procedure ◽  
Time Point

On 2 July 2021, highly negative results were reported from the POLAR A and M phase III trials in patients with colorectal cancer, treated with an oxaliplatin-based regimen and co-treated with calmangafodipir (CaM; PledOx®; PledPharma AB/Egetis Therapeutics AB) or placebo. The results revealed persistent chemotherapy-induced peripheral neuropathy (CIPN) in 54.8% of the patients treated with PledOx, compared with 40.0% of the patients treated with the placebo (p < 0.05), i.e., a 37% increase in incidence of the side effect that the trial was aimed to prevent. The damaging outcome of the trials differed diametrically from an in-parallel conducted mice study and from a clinical trial with mangafodipir, the active ingredient of CaM. According to the authors of the POLAR report, the etiology of the profound increase in CIPN in the PledOx arm is unclear. However, these devastating effects are presumably explained by intravenous administrations of PledOx and oxaliplatin being too close in time and, thereby, causing unfavorable redox interactions between Mn2+ and Pt2−. In the mice study as well as in the preceding phase II clinical trial (PLIANT), PledOx was administered 10 min before the start of the oxaliplatin infusion; this was clearly an administration procedure, where the devastating interactions between PledOx and oxaliplatin could be avoided. However, when it comes to the POLAR trials, PledOx was administered, for incomprehensible reasons, “on Top of Modified FOLFOX6” at day one, i.e., after the two-hour oxaliplatin infusion instead of before oxaliplatin. This is a time point when the plasma concentration of oxaliplatin and Pt2+-metabolites is at its highest, and where the risk of devastating redox interactions between PledOx and oxaliplatin, in turn, is at its highest.

Chemotherapy for patients with advanced gastric cancer with performance status 2

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15627-e15627
Author(s):  
K. Muro ◽  
K. Shitara ◽  
T. Ura ◽  
D. Takahari ◽  
T. Yokota ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Clinical Trial ◽  
Mortality Rate ◽  
Treatment Failure ◽  
Performance Status ◽  
Phase Iii ◽  
Treatment Results ◽  
Time To Treatment Failure ◽  
Phase Iii Trials ◽  
Line Chemotherapy

e15627 Background: S-1 plus cisplatin is considered to be the standard chemotherapy for Japanese patients with advanced gastric cancer (AGC) according to the results of three phase III trials (JCOG9912/SPIRITS/TOP-002). However, since few patients with poor performance status (PS2) were included in these phase III trials (27 of 1317; 2%), the standard treatment of patients with PS2 has not been established yet. In also, the characteristics and prognosis of AGC patients with PS2 has not been reported in detail. Methods: We retrospectively analyzed 545 patients with AGC treated by chemotherapy during the period from January 2003 to June 2008. Patients characteristic and treatment results were compared between PS0–1 and PS2. Results: At the beginning of 1st-line chemotherapy, PS0–1/2/3–4 was 454/69/22 cases respectively. Patients with peritoneal/pleural dissemination was more common in PS2 than PS0–1 (75% vs. 43%, p<0.001). Patients with multiple metastatic places was more common in PS2 (62% vs. 43%; p=0.007). Fewer patients in PS2 were registered in clinical trial (1.4% vs. 25%, p<0.001). First-line chemotherapy using oral drug (S- 1/capecitabine) was significantly fewer in PS2 (43% vs. 75%, P<0.001). Median time to treatment failure was significantly shorter in PS2 (2.3 months vs. 4.2 months, p<0.001). Patients who could receive second-line chemotherapy were significantly fewer in PS2 (50% vs. 75%, p<0.001). With the median follow up time of 42 months, median survival time of patients with PS0–1 was 14.8 months (95% CI;13.1–16.5) and that of patients with PS2 was 6.1 months (4.3 to 7.4 months; hazard ratio for death 3.0: 95% CI2.3–4.0; p<0.001). Mortality rate within 30 days was higher in PS2 (3% vs. 0.2%; p<0.001). Conclusions: AGC patients with PS2 had not only had poor prognosis compared with PS0–1 but also had fewer chance of registration in the clinical trial, shorter time to treatment failure, and higher mortality rate within 30 days. Considering these different characteristics and treatment results of PS0–1 and PS2, clinical trial especially targeting AGC patients with PS2 is necessary to evaluate optimal chemotherapeutic regimens for PS2 patients. No significant financial relationships to disclose.

Clinical trial risk reduction in non-small cell lung cancer though the use of biomarkers and receptor-targeted therapies.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8040-8040
Author(s):  
Adam Falconi ◽  
Gilberto Lopes ◽  
Jayson L. Parker
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Drug Development ◽  
Phase I ◽  
Success Rate ◽  
Targeted Therapies ◽  
Phase Iii ◽  
Clinical Testing ◽  
Phase Ii Trials ◽  
Phase Iii Trials

8040 Background: We analyzed the risk of clinical trial failure duringnon-small cell lung cancer (NSCLC) drug development between 1998 and 2012. Methods: NSCLC drug development was investigated using trial disclosures from publically available resources. Compounds were excluded from the analysis if they began phase I clinical testing before 1998 and if they did not use treatment relevant endpoints. Analysis was conducted in regards to treatment indication, compound classification and mechanism of action. Costs of clinical drug development for advanced NSCLC were calculated using industry data and assumptions, a 9% yearly discount rate and assuming a clinical trial length of 2.5 years for phase I trials, 4 years for phase II trials, 5 years for phase III trials and an average of 5 phase I trials, 7 phase II trials, and 4 phase III trials per approved drug. All funding costs are in US dollars (USD). Results: 2,407 clinical trials met search criteria. 676 trials and 199 unique compounds met our inclusion criteria. The likelihood, or cumulative clinical trial success rate, that a new drug would pass all phases of clinical testing and be approved was found to be 11%, which is less than the expected industry aggregate rates (16.5%). The success of phase III trials was found to be the biggest obstacle for drug approval with a success rate of only 28%. Biomarker-guided targeted therapies (with a success rate of 62%) and receptor targeted therapies (with a success rate of 31%) were found to have the highest likelihood of success in clinical trials. The risk-adjusted cost for NSCLC clinical drug development was calculated to be 1.89 billion US dollars. Use of biomarkers decreased drug development cost by 26% to 1.4 billion US dollars. Potential savings may be even higher if fewer clinical trials are required for successful development. Conclusions: Physicians that enroll patients in NSCLC trials should prioritize their participation in clinical trial programs that involve either a biomarker or receptor targeted therapy, which appear to carry the best chances for a successful treatment response. Given the high adjusted cost of clinical testing alone in NSCLC, efforts to mitigate the risk of trial failure need to explore these factors more fully.

Sign in / Sign up

Export Citation Format

Share Document