scholarly journals Central Pathology Review for Phase III Clinical Trials: The Enabling Effect of Virtual Microscopy

2013 ◽  
Vol 137 (4) ◽  
pp. 492-495 ◽  
Author(s):  
Pawel Mroz ◽  
Anil V. Parwani ◽  
Piotr Kulesza
Keyword(s):  
Clinical Trials ◽  
Control Measure ◽  
Substantial Reduction ◽  
Virtual Microscopy ◽  
Turnaround Time ◽  
Phase Iii ◽  
Advantages And Disadvantages ◽  
Number Of Patients ◽  
Central Pathology ◽  
Pathology Review

Context.—Central pathology review (CPR) was initially designed as a quality control measure. The potential of CPR in clinical trials was recognized as early as in the 1960s and quickly became embedded as an integral part of many clinical trials since. Objective.—To review the current experience with CPR in clinical trials, to summarize current developments in virtual microscopy, and to discuss the potential advantages and disadvantages of this technology in the context of CPR. Data Sources.—A PubMed (US National Library of Medicine) search for published studies was conducted, and the relevant articles were reviewed, accompanied by the authors' experience at their practicing institution. Conclusions.—The review of the available literature strongly suggests the growing importance of CPR both in the clinical trial setting as well as in second opinion cases. However, the currently applied approach significantly impedes efficient transfer of slides and patient data. Recent advances in imaging, digital microscopy, and Internet technologies suggest that the CPR process may be dramatically streamlined in the foreseeable future to allow for better diagnosis and quality assurance than ever before. In particular, whole slide imaging may play an important role in this process and result in a substantial reduction of the overall turnaround time required for slide review at the central location. Above all, this new approach may benefit the large clinical trials organized by oncology cooperative groups, since most of those trials involve complicated logistics owing to enrollment of large number of patients at several remotely located participating institutions.

Trends in case-control allocation in phase III randomized cancer clinical trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14582-e14582
Author(s):  
Shruti Gupta ◽  
Swathi Gopishetty ◽  
Srishti Malhotra ◽  
Vamsi Kota ◽  
Anand P. Jillella ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Trial Design ◽  
Phase Iii ◽  
Cancer Clinical Trials ◽  
Unequal Distribution ◽  
Equal Distribution ◽  
Advantages And Disadvantages ◽  
Significant Difference ◽  
And Control ◽  
Unequal Allocation

e14582 Background: Patients enrollment in cancer clinical trials has traditionally been limited to an equal distribution between cases and controls. Some clinical trials have an unequal distribution between the case and control arm. Although such unequal allocation is uncommon it has certain advantages and disadvantages to it. The trend and proportion of cancer clinical trials that have an unequal allocation has not been studied. Methods: Data about cancer clinical trials was extracted from clinical trials.gov. The query included phase 3 trials which included adults and were conducted between 2010 to 2017. Only clinical trials that were either completed or active – but not recruiting were included. T test was used to determine statistical difference between different subgroups. Results: 601 clinical trials were identified of which 356 trials with two arms and 47 trials with 3+ arms were identified. Amongst the eligible 298 trials with two arms, there were 216 trials with equal allocation (1:1) and 82 trials with unequal allocation. Amongst the eligible 29 trials with 3+ arms; there were 21 trials with equal allocation (1:1:1) and 8 trials with unequal allocation. There was no significant difference in the proportion of trials with unequal allocation over the time period from 2010 to 2017. The categories of cancer which had the highest number of two arm clinical trials with unequal allotment were: genitourinary, breast and hematological malignancies (Table). Conclusions: Cancer clinical trials with unequal allocation between case and control arms have been common in the past decade. This may represent a new trend in clinical trial design to help enhance closer monitoring of adverse events despite higher costs attached to this method.[Table: see text]

scholarly journals Nationwide incidence of sarcomas and connective tissue tumors of intermediate malignancy over four years using an expert pathology review network

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246958
Author(s):  
Gonzague de Pinieux ◽  
Marie Karanian ◽  
Francois Le Loarer ◽  
Sophie Le Guellec ◽  
Sylvie Chabaud ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Characteristics ◽  
Who Classification ◽  
Phase Iii ◽  
Histological Subtypes ◽  
Phase Ii Clinical Trials ◽  
Yearly Incidence ◽  
Independent Review ◽  
Low Incidence ◽  
Pathology Review

Background Since 2010, nationwide networks of reference centers for sarcomas (RREPS/NETSARC/RESOS) collected and prospectively reviewed all cases of sarcomas and connective tumors of intermediate malignancy (TIM) in France. Methods The nationwide incidence of sarcoma or TIM (2013–2016) was measured using the 2013 WHO classification and confirmed by a second independent review by expert pathologists. Simple clinical characteristics, yearly variations and correlation of incidence with published clinical trials are presented and analyzed. Results Over 150 different histological subtypes are reported from the 25172 patients with sarcomas (n = 18712, 74,3%) or TIM (n = 6460, 25.7%), with n = 5838, n = 6153, n = 6654, and n = 6527 yearly cases from 2013 to 2016. Over these 4 years, the yearly incidence of sarcomas and TIM was therefore 70.7 and 24.4 respectively, with a combined incidence of 95.1/106/year, higher than previously reported. GIST, liposarcoma, leiomyosarcomas, undifferentiated sarcomas represented 13%, 13%, 11% and 11% of tumors. Only GIST, as a single entity had a yearly incidence above 10/106/year. There were respectively 30, 64 and 66 different histological subtypes of sarcomas or TIM with an incidence ranging from 10 to 1/106, 1–0.1/106, or < 0.1/106/year respectively. The 2 latter incidence groups represented 21% of the patients with 130 histotypes. Published phase III and phase II clinical trials (p<10−6) are significantly higher with sarcomas subtypes with an incidence above 1/106 per. Conclusions This nationwide registry of sarcoma patients, with exhaustive histology review by sarcoma experts, shows that the incidence of sarcoma and TIM is higher than reported, and that tumors with a very low incidence (1<106/year) are less likely to be included in clinical trials.

An analysis of target-specific patient resource utilization in NSCLC clinical trials.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18112-e18112
Author(s):  
Neeta Somaiah ◽  
George R. Simon
Keyword(s):  
Clinical Trials ◽  
Resource Utilization ◽  
Phase Iii ◽  
Clinical Testing ◽  
Targeted Agents ◽  
Specific Patient ◽  
New Targets ◽  
Number Of Patients ◽  
Nsclc Patients ◽  
The Impact

e18112 Background: A plethora of targeted agents are currently being evaluated in patients with NSCLC. The number of targeted agents exceeds the number of targets leading to many targeted agents being evaluated against similar targets. The identification of new targets are likely to increase exponentially in the near future given the numerous currently ongoing molecular profiling efforts. The objective of this analysis is to estimate the target-specific patient resource utilization and its impact on routine clinical care. Methods: A comprehensive search for molecularly targeted agents in clinical testing that have accrued or are accruing NSCLC patients were performed by using publically available search engines and databases. Agents were grouped according to the primary target and the phase of development. We computed the number of patients allocated to completed and ongoing phase III NSCLC trials for advanced NSCLC alone. Results: There are more than 30 categories of molecular targets accruing NSCLC patients in clinical trials. By conservative estimates, approximately 215 agents are currently undergoing clinical testing. The median number of agents per target is 7 (range 2 (HIF-1α and PDGFRα) – 24 (EGFR)). There are 7 EGFR inhibitors and 10 VEGFR inhibitors that were evaluated in phase III trials; with 36,093 and 20,313 stage IV NSCLC patients enrolled or to be enrolled in these trials, respectively. No more than 2 agents per target have been FDA approved for NSCLC to date. Further details of the analyses will be more comprehensively presented at the meeting. Conclusions: Patient resource utilization is unevenly distributed across targets. The optimal number of targeted agents to be evaluated per target remains to be defined. More emphasis on identifying new targets and targeting these with limited number of optimal agents may accelerate the advancement of the field and the impact on patient care.

Comparing the ability of various compositive outcomes to discriminate treatment effects in MS clinical trials

1998 ◽  
Vol 4 (6) ◽  
pp. 480-486 ◽  
Author(s):  
D E Goodkin ◽  
R L Priore ◽  
K E Wende ◽  
M Campion ◽  
D N Bourdette ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Treatment Failure ◽  
Treatment Effects ◽  
Manual Dexterity ◽  
Phase Iii ◽  
Kaplan Meier ◽  
Number Of Patients ◽  
Disability Status ◽  
Phase Iii Study ◽  
Block Test

We compared the ability of the Kurtzke Expanded Disability Status Scale (EDSS) and a composite outcome of non-physician-based measures of time to ambulate 25 feet (TA) and manual dexterity (the Box and Block Test [BBT], and 9-Hole Peg Test [9HPT]) to discriminate treatment effects in the Phase III study of interferon beta-1a. A log-rank comparison of Kaplan-Meier curves by treatment group showed the non-physicianbased composite of BBT, 9HPT, and TA was of comparable sensitivity (P=0.013) in discriminating sustained treatment failure as the EDSS alone (P=0.029). The composite of BBT, 9HPT, TA, and EDSS was more sensitive (P=0.009) in discriminating sustained treatment failure than the EDSS alone. Compositive outcomes of the EDSS and non-physician-based measures of manual dexterity and timed ambulation provide an appealing strategy to reduce the number of patients required to discriminate treatment effects in MS clinical trials.

scholarly journals Regulatory delays in a multinational clinical stroke trial

2021 ◽  
pp. 239698732110048
Author(s):  
Jeroen C de Jonge ◽  
Hendrik Reinink ◽  
Bridget Colam ◽  
Iris Alpers ◽  
Alfonso Ciccone ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Regulatory Authority ◽  
Recruitment Rate ◽  
Phase Iii ◽  
Randomised Clinical Trials ◽  
Patient Recruitment ◽  
Trial Site ◽  
Number Of Patients ◽  
Clinical Stroke Trial

Introduction The initiation and conduct of randomised clinical trials are complicated by multiple barriers, including delays in obtaining regulatory approvals. Quantitative data on the extent of the delays due to national or local review in randomised clinical trials is scarce. Materials and methods We assessed the times needed to obtain regulatory approval and to initiate a trial site for an academic, EU-funded, phase III, randomised clinical trial of pharmacological prevention of complications in patients with acute stroke in over 80 sites in nine European countries. The primary outcome was the time from the first submission to a regulatory authority to initiation of a trial site. Secondary outcomes included time needed to complete each individual preparatory requirement and the number of patients recruited by each site in the first 6 and 12 months. Results The median time from the first submission to a regulatory authority to initiation of a trial site was 784 days (IQR: 586–1102). The single most time-consuming step was the conclusion of a clinical trial agreement between the national coordinator and the trial site, which took a median of 194 days (IQR: 93–293). A longer time to site initiation was associated with a lower patient recruitment rate in the first six months after initiation (B = –0.002; p = 0.02). Discussion Conclusion In this EU-funded clinical trial, approximately 26 months were needed to initiate a trial site for patient recruitment. The conclusion of a contract with a trial site was the most time-consuming activity. To simplify and speed up the process, we suggest that the level of detail of contracts for academic trials should be proportional to the risks and commercial interests of these trials.

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.

Relapse rate after adjuvant trastuzumab in the northeast of Italy: Preliminary data from a multicenter observational study in a clinical setting.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 586-586 ◽  
Author(s):  
Giorgio Mustacchi ◽  
Annamaria Molino ◽  
Elena Fiorio ◽  
Antonella Brunello ◽  
Vittorina Zagonel ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Relapse Rate ◽  
Metastatic Disease ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Adjuvant Trastuzumab ◽  
Multicenter Observational Study ◽  
North East ◽  
Number Of Patients

586 Background: Relapse Rate (RR) after adjuvant trastuzumab (AT) reported in clinical trials is between 15 and 21%. Information on RR and clinical behaviour of HER2-POS metastatic disease after AT outside clinical trials is limited. At ASCO Meeting 2010 RR was reported 8% (Abs 1080) to 10% (Abs 684), with a Survival Post Progression (SPP) of 8.8 and 5.7 months, respectively. It is useful to increase informations about metastatic HER2-POS disease after AT, outside clinical trials. Methods: HER2-POS consecutive cases treated with AT in 6 Hospitals of North East Italy were anonymously collected and merged. The following data were analyzed: Stage, ER/PgR Status, Chemotherapy regimens (CHT) , follow up, RR, Disease Free Survival (DFS), Overall Survival (OS) and SPP. Results: The number of patients was 413, median age 55 (24-84). Anatomic Stage was I in 39.7%, II in 40,3%, III in 24.4%. ER/PgR neg cases were 164 (41.6%). Given CHT were Anthra-based 33.4% and Anthra-Taxane 54.5%. At a mean follow up of 35 months (7-115) RR was 10.8% (45 cases), with a mean DFS of 23.8 months (3.2-74). Among relapsed patients, 37/45 (82.2%) had ER/PgR neg tumors. One patient died NED for CHF and 22 for metastatic disease, with a mean OS of 37.1 months (10.2-87.9). Mean SPP was 17.8 months. According to DFS <12 mos , >12<24 and >24, mean OS was 31.3, 31.7 and 56.12(p=0.03) months; SPP was 24.2, 14.4 and 17.8 months, respectively. Conclusions: In our experience RR after AT is lower than in published Phase III clinical trials. ER/PgR neg status seems a negative prognostic factor (82.2% in the relapsed population vs 41.6% overall). OS is similar for patients relapsed within 24 months but SPP is 10 months longer in very early relapses. Relapse after 2 years is correlated with a long OS (nearly 5 years), with SPP shorter vs early relapse (17.8 vs 24.2 months). Our preliminary results suggest different disease behaviors in relapsed HER2-POS Breast Cancer after AT, with different DFS and SPP, suggesting a different effect of further therapies. Considering the small RR, the study target accrual is proceeding to collect up to more than 1000 AT treated patients, including post-progression treatments, not available at the moment.

A phase II trial design with direct assignment option for initial marker validation.

2012 ◽  
Vol 30 (30_suppl) ◽  
pp. 34-34 ◽  
Author(s):  
Sumithra J. Mandrekar ◽  
Ming-Wen An ◽  
Daniel J. Sargent
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Type I Error ◽  
Predictive Biomarkers ◽  
Stage Ii ◽  
Phase Iii ◽  
Type I ◽  
Design Strategies ◽  
Number Of Patients ◽  
The Impact

34 Background: Phase II clinical trials aim to identify promising experimental regimens for further testing in phase III trials. Testing targeted therapies with predictive biomarkers mandates efficient trial designs. Current biomarker-based trial designs, including the enrichment, all-comers, and adaptive designs, randomize patients to receive treatment or not throughout the entire duration of the trial. Recognizing the need for randomization yet acknowledging the possibility of promising but nonconclusive results after a preplanned interim analysis (IA), we propose a two-stage phase II design that allows for the possibility of direct assignment (i.e., stop randomization and assign all patients to the experimental arm in stage II) based on IA results. Methods: Using simulations, we compared properties of the direct assignment option design to a 1:1 randomized phase II design and assessed the impact of the timing of IA (after 33%, 50%, or 67% of accrual) and number of IA (one versus two with option for direct assignment at the first and second) over a range of response rate ratios (between 1.0 and 3.0). Results: Between 12% and 30% of the trials (out of 6,000 simulated trials) adopt direct assignment in stage II, with direct adoption depending on the treatment effect size and specified type I error rate (TIER). The direct assignment option design has minimal loss in power (<1.8%) and minimal increase in T1ER (<2.1%) compared to a 1:1 randomized design. The maximum loss in power across possible timings of IA was <1.2%. For the direct assignment option design, there was a 20%-50% increase in the number of patients treated on the experimental (vs. control) arm for the 1 IA case, and 40%-100% increase for the 2 IA case. Conclusions: Testing predictive biomarkers in clinical trials requires new design strategies. In the spectrum of phase II designs from adaptive to balanced randomized all-comers or enrichment designs, the direct assignment design provides a middle ground with desirable statistical properties that may appeal to both clinicians and patients.

Nationwide incidence of sarcomas and tumors of intermediate malignancy in the NETSARC network with central pathology review: Correlation with published clinical research.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11560-11560
Author(s):  
Gonzague De Pinieux ◽  
Marie Karanian ◽  
Francois Le Loarer ◽  
Sophie Le Guellec ◽  
Philippe Terrier ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Who Classification ◽  
Phase Iii ◽  
Tumor Board ◽  
Histological Subtypes ◽  
Phase Ii Clinical Trials ◽  
Yearly Incidence ◽  
Pathological Review ◽  
Central Pathology ◽  
Expert Network

11560 Background: Since 2010, presentation to a designated sarcoma tumor board and pathological review by an expert network are mandatory for sarcoma patients in France. NETSARC+ (merging the 3 initial RREPS, RESOS & NETSARC) collected prospectively all cases of reviewed sarcomas and tumors of intermediate malignancy (TIM) nationwide. We report on the incidence of subtypes according to WHO classification from 2013 to 2016. Methods: Sarcoma expert pathologists reviewed samples were all prospectively integrated in the database; the results using the latest WHO classification are presented for the years 2013 to 2016, including yearly variations. Correlation of the incidence of each histotype with dedicated published clinical trials was conducted. Results: 139 different histological subtypes are reported among the 25172 patients with sarcomas (n = 18710, 64%) or TIM (n = 6460, 36%), respectively n = 5838, n = 6153, n = 6654, and n = 6527 yearly from 2013 to 2016. Over these 4 years, the observed yearly incidence of sarcomas, TIM, and all was therefore 79.7, 24.9 and 95.1/10e6/year, above that previously reported. GIST, liposarcoma, leiomyosarcomas, undifferentiated sarcomas represented 13%, 13%, 11% and 11% of all sarcomas. Only GIST, as a single entity exceeded a yearly incidence above 10/million per year. There were respectively 30, 63 and 66 different histological subtypes of sarcomas or TIM (single entities or lumped together, e.g. MPNST, or vascular sarcomas...) with an incidence ranging from 10 to 1/10e6/year, 1-0.1/10e6 per year, or < 0.1/10e6/year respectively. The 2 later “incidence groups” included 21% of the patients. The incidence of 8 histotypes varied significantly over this 4 years. Patients with tumors with an incidence above 1/10e6 per year have significantly higher numbers of dedicated published phase III and phase II clinical trials (p < 10e-6). Conclusions: This nationwide registry of sarcoma patients with an histology reviewed by sarcoma experts shows that the incidence of sarcoma and TIM is higher than previously reported, may vary over years for some histotypes, and that tumors with an incidence < 10e6 have a much lower access to clinical trials.

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