scholarly journals Using phase II data for the analysis of phase III studies: An application in rare diseases

2017 ◽  
Vol 14 (3) ◽  
pp. 277-285 ◽  
Author(s):  
Simon Wandel ◽  
Beat Neuenschwander ◽  
Christian Röver ◽  
Tim Friede
Keyword(s):  
Drug Development ◽  
Phase Ii ◽  
Interim Analysis ◽  
Large Scale ◽  
Drug Approval ◽  
Phase Iii ◽  
Orphan Diseases ◽  
Operating Characteristics ◽  
Phase Iii Study ◽  
Phase Iii Studies

Background: Clinical research and drug development in orphan diseases are challenging, since large-scale randomized studies are difficult to conduct. Formally synthesizing the evidence is therefore of great value, yet this is rarely done in the drug-approval process. Phase III designs that make better use of phase II data can facilitate drug development in orphan diseases. Methods: A Bayesian meta-analytic approach is used to inform the phase III study with phase II data. It is particularly attractive, since uncertainty of between-trial heterogeneity can be dealt with probabilistically, which is critical if the number of studies is small. Furthermore, it allows quantifying and discounting the phase II data through the predictive distribution relevant for phase III. A phase III design is proposed which uses the phase II data and considers approval based on a phase III interim analysis. The design is illustrated with a non-inferiority case study from a Food and Drug Administration approval in herpetic keratitis (an orphan disease). Design operating characteristics are compared to those of a traditional design, which ignores the phase II data. Results: An analysis of the phase II data reveals good but insufficient evidence for non-inferiority, highlighting the need for a phase III study. For the phase III study supported by phase II data, the interim analysis is based on half of the patients. For this design, the meta-analytic interim results are conclusive and would justify approval. In contrast, based on the phase III data only, interim results are inconclusive and require further evidence. Conclusion: To accelerate drug development for orphan diseases, innovative study designs and appropriate methodology are needed. Taking advantage of randomized phase II data when analyzing phase III studies looks promising because the evidence from phase II supports informed decision-making. The implementation of the Bayesian design is straightforward with public software such as R.

Comparison of Outcomes of Phase II Studies and Subsequent Randomized Control Studies Using Identical Chemotherapeutic Regimens

2005 ◽  
Vol 23 (28) ◽  
pp. 6982-6991 ◽  
Author(s):  
Mohammad I. Zia ◽  
Lillian L. Siu ◽  
Greg R. Pond ◽  
Eric X. Chen
Keyword(s):  
Phase Ii ◽  
English Language ◽  
Response Rates ◽  
Phase Iii ◽  
Positive Phase ◽  
Phase Ii Studies ◽  
Solid Malignancies ◽  
Study Characteristics ◽  
Phase Iii Study ◽  
Phase Iii Studies

Purpose To determine whether promising results from phase II studies could be reproduced in phase III studies, and to examine which characteristics of phase II studies might be of predictive value for subsequent phase III studies. Methods We searched for all phase III studies of chemotherapy in advanced solid malignancies, published in the English language literature from July 1998 to June 2003. Each phase III study was reviewed to identify preceding phase II studies. Phase II and phase III studies included in this analysis must have used identical regimens. Data were extracted from both phase II and phase III studies. Results Of 181 phase III studies identified, 43 used therapeutic regimens identical to those in 49 preceding phase II studies. Twelve phase III studies (28%) were “positive.” The vast majority (81%) of phase III studies have lower response rates than preceding phase II studies, with a mean difference of 12.9% among all studies analyzed. None of the phase II study characteristics evaluated significantly predicted for “positive” phase III studies, but the sample size of phase II studies demonstrated a trend toward being predictive (P = .083). Conclusion Promising results from phase II studies frequently do not translate into “positive” phase III studies. Response rates in most phase III studies are lower than those in preceding phase II studies.

Model-Based Prediction of Phase III Overall Survival in Colorectal Cancer on the Basis of Phase II Tumor Dynamics

2009 ◽  
Vol 27 (25) ◽  
pp. 4103-4108 ◽  
Author(s):  
Laurent Claret ◽  
Pascal Girard ◽  
Paulo M. Hoff ◽  
Eric Van Cutsem ◽  
Klaas P. Zuideveld ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Survival Time ◽  
Phase Ii ◽  
Tumor Size ◽  
Prediction Interval ◽  
Phase Iii ◽  
Antitumor Response ◽  
Phase Iii Study ◽  
Phase Iii Studies ◽  
Size Data

PurposeWe developed a drug-disease simulation model to predict antitumor response and overall survival in phase III studies from longitudinal tumor size data in phase II trials.MethodsWe developed a longitudinal exposure-response tumor-growth inhibition (TGI) model of drug effect (and resistance) using phase II data of capecitabine (n = 34) and historical phase III data of fluorouracil (FU; n = 252) in colorectal cancer (CRC); and we developed a parametric survival model that related change in tumor size and patient characteristics to survival time using historical phase III data (n = 245). The models were validated in simulation of antitumor response and survival in an independent phase III study (n = 1,000 replicates) of capecitabine versus FU in CRC.ResultsThe TGI model provided a good fit of longitudinal tumor size data. A lognormal distribution best described the survival time, and baseline tumor size and change in tumor size from baseline at week 7 were predictors (P < .00001). Predicted change of tumor size and survival time distributions in the phase III study for both capecitabine and FU were consistent with observed values, for example, 431 days (90% prediction interval, 362 to 514 days) versus 401 days observed for survival in the capecitabine arm. A modest survival improvement of 39 days (90% prediction interval, −21 to 110 days) versus 35 days observed was predicted for capecitabine.ConclusionThe modeling framework successfully predicted survival in a phase III trial on the basis of capecitabine phase II data in CRC. It is a useful tool to support end-of-phase II decisions and design of phase III studies.

9088 Phase III study of Lipoplatin plus Gemcitabine versus Cisplatin plus Gemcitabine in advanced NSCLC; interim analysis

2009 ◽  
Vol 7 (2) ◽  
pp. 531 ◽  
Author(s):  
C. Kosmas ◽  
J. Angel ◽  
A. Athanasiou ◽  
A. Rapti ◽  
C. Karanikas ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Advanced Nsclc ◽  
Phase Iii ◽  
Phase Iii Study

Hydrogeological Characterization Based on Long Term Groundwater Pressure Monitoring

2010 ◽  
Author(s):  
Shuji Daimaru ◽  
Ryuji Takeuchi ◽  
Masaki Takeda ◽  
Masayuki Ishibashi
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Large Scale ◽  
Pumping Test ◽  
Phase Iii ◽  
Pressure Monitoring ◽  
Energy Agency ◽  
Hydrogeological Characteristics ◽  
Under Construction

The Mizunami Underground Research Laboratory (MIU) is now under construction by the Japan Atomic Energy Agency in the Tono area of central Japan. The MIU project is being implemented in three overlapping Phases: Surface-based Investigation (Phase I), Construction (Phase II) and Operation (Phase III). The changes of groundwater pressure due to shaft excavation can be considered analogous to a large-scale pumping test. Therefore, there is the possibility that the site scale groundwater field (several km square) can be approximated by the long-term groundwater pressure monitoring data from Phase II. Based on the monitoring observations, hydrogeological characteristics were estimated using the s-log(t/r2) plot based on the Cooper-Jacob straight line method. Results of the s-log(t/r2) plots are as follows. The groundwater flow field around the MIU construction site is separated into domains by an impermeable fault. In other words, the fault is a hydraulic barrier. Hydraulic conductivity calculated from s-log(t/r2) plots are in the order of 1.0E−7(m/s). The above results from the long term monitoring during Phase II are a verification of the hydrogeological characteristics determined in the Phase I investigations.

Phase II testing of melphalan in children with newly diagnosed rhabdomyosarcoma: a model for anticancer drug development.

1988 ◽  
Vol 6 (2) ◽  
pp. 308-314 ◽  
Author(s):  
M E Horowitz ◽  
E Etcubanas ◽  
M L Christensen ◽  
J A Houghton ◽  
S L George ◽  
...  
Keyword(s):  
Phase Ii ◽  
Drug Disposition ◽  
Clinical Performance ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Heavily Pretreated ◽  
Phase Iii Study ◽  
Successful Testing ◽  
Previously Treated Patients ◽  
Pretreated Patients

We describe events that led to successful testing of melphalan, one of the nitrogen mustard compounds, in children with newly diagnosed, poor-risk rhabdomyosarcoma (RMS). Preclinical studies with xenografts of human RMS, growing in the flanks of immune-deprived mice, had indicated superior oncolytic activity by melphalan compared with other agents commonly used to treat this tumor. However, in a conventional phase II trial, melphalan failed to produce partial responses in 12 of 13 heavily pretreated patients with recurrent tumors. Subsequent comparison of the drug's pharmacokinetics in mice and patients indicated that its poor clinical performance was not the result of interspecies differences in drug disposition. Therefore, we elected to retest melphalan in untreated patients, before they were enrolled in a phase III study. Of 13 children who received the drug for 6 weeks, ten had partial responses, confirming the significant antitumor activity seen in the xenograft system. These findings illustrate the inherent limitations of phase II drug trials in previously treated patients and suggest a useful paradigm for the development of antineoplastic drugs.

Randomized Multicenter Phase II Trial of a Biweekly Regimen of Fluorouracil and Leucovorin (LV5FU2), LV5FU2 Plus Cisplatin, or LV5FU2 Plus Irinotecan in Patients With Previously Untreated Metastatic Gastric Cancer: A Fédération Francophone de Cancérologie Digestive Group Study—FFCD 9803

2004 ◽  
Vol 22 (21) ◽  
pp. 4319-4328 ◽  
Author(s):  
Olivier Bouché ◽  
Jean Luc Raoul ◽  
Franck Bonnetain ◽  
Marc Giovannini ◽  
Pierre Luc Etienne ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Progression Free Survival ◽  
Metastatic Gastric Cancer ◽  
Phase Iii ◽  
Survival Times ◽  
Multicenter Phase ◽  
Independent Expert ◽  
Phase Iii Study ◽  
Cancérologie Digestive

Purpose To determine the efficacy and safety of a biweekly regimen of leucovorin (LV) plus fluorouracil (FU) alone or in combination with cisplatin or irinotecan in patients with previously untreated metastatic gastric adenocarcinoma and to select the best arm for a phase III study. Patients and Methods One hundred thirty-six patients (two were ineligible) were enrolled onto the randomized multicenter phase II trial. Patients received LV 200 mg/m2 (2-hour infusion) followed by FU 400 mg/m2 (bolus) and FU 600 mg/m2 (22-hour continuous infusion) on days 1 and 2 every 14 days (LV5FU2; arm A), LV5FU2 plus cisplatin 50 mg/m2 (1-hour infusion) on day 1 or 2 (arm B), or LV5FU2 plus irinotecan 180 mg/m2 (2-hour infusion) on day 1 (arm C). Results The overall response rates, which were confirmed by an independent expert panel, were 13% (95% CI, 3.4% to 23.3%), 27% (95% CI, 14.1% to 40.4%), and 40% (95% CI, 25.7% to 54.3%) for arms A, B, and C, respectively. Median progression-free survival and overall survival times were 3.2 months (95% CI, 1.8 to 4.6 months) and 6.8 months (95% CI, 2.6 to 11.1 months) with LV5FU2, respectively; 4.9 months (95% CI, 3.5 to 6.3 months) and 9.5 months (95% CI, 6.9 to 12.2 months) with LV5FU2-cisplatin, respectively; and 6.9 months (95% CI, 5.5 to 8.3 months) and 11.3 months (95% CI, 9.3 to 13.3 months) with LV5FU2-irinotecan, respectively. Conclusion Of the three regimens tested, the combination of LV5FU2-irinotecan is the most promising and will be assessed in a phase III trial.

RE-COVERY DVT/PE: Rationale and design of a prospective observational study of acute venous thromboembolism with a focus on dabigatran etexilate

2017 ◽  
Vol 117 (02) ◽  
pp. 415-421 ◽  
Author(s):  
Walter Ageno ◽  
Ivan B. Casella ◽  
Chee Kok Han ◽  
Gary E. Raskob ◽  
Sebastian Schellong ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Vitamin K ◽  
Large Scale ◽  
Vitamin K Antagonists ◽  
Phase 1 ◽  
Dabigatran Etexilate ◽  
Oral Anticoagulants ◽  
Phase Iii ◽  
Real World Data ◽  
Phase Iii Studies

SummaryThe therapeutic management of venous thromboembolism (VTE) is rapidly evolving. Following the positive results of pivotal large-scale randomised trials, the non-vitamin K antagonist oral anticoagulants (NOACs) represent an important alternative to standard anticoagulation. In phase III studies, dabigatran was as effective as, and significantly safer than warfarin. Additional information on real-world data of dabigatran is now warranted. RE-COVERY DVT/PE is a multi-centre, international, observational (i. e. non-interventional) study enrolling patients with acute DVT and/or PE within 30 days after objective diagnosis. The study is designed with two phases. Phase 1 has a cross-sectional design, enrolling approximately 6000 patients independently of treatment choice, with the aim of providing a contemporary picture of the management of VTE worldwide. Phase 2 has a prospective cohort design, with follow-up of one year, enrolling 8000 patients treated with dabigatran or vitamin K antagonists (VKAs) with the aim of comparing their safety, defined by the occurrence of major bleeding, and effectiveness, defined by the occurrence of symptomatic recurrent VTE. RE-COVERY DVT/PE will complement both the results of other observational studies in this field and the results of phase III studies with dabigatran, in particular by assessing its clinical benefit in various patient subgroups treated in routine clinical practice.

Phase II Window of Idarubicin in Children With Extraocular Retinoblastoma

1999 ◽  
Vol 17 (6) ◽  
pp. 1847-1847 ◽  
Author(s):  
Guillermo L. Chantada ◽  
Adriana Fandiño ◽  
Gabriel Mato ◽  
Sandra Casak
Keyword(s):  
Bone Marrow ◽  
Phase Ii ◽  
Progressive Disease ◽  
Bone Marrow Involvement ◽  
Complete Response ◽  
Phase Iii ◽  
Starting Dose ◽  
Hematopoietic Toxicity ◽  
Grade 3 ◽  
Phase Iii Studies

PURPOSE: The aim of this study was to evaluate in an upfront phase II study the response to idarubicin in children with extraocular retinoblastoma. PATIENTS AND METHODS: The starting dose of idarubicin was 15 mg/m2/d (days 1 and 2) weeks 0 and 3. After an interim evaluation, the dose was reduced to 10 mg/m2/d (days 1 and 2) weeks 0 and 3 because of hematopoietic toxicity. Response was evaluated at week 6. RESULTS: At the Hospital JP Garrahan (Buenos Aires, Argentina), 10 patients (five bilateral) were entered onto the study from 1995 to 1998. A total of 19 cycles were administered. Extraocular sites included orbit (n = 10), bone marrow (n = 3), bone (n = 1), lymph node (n = 1), and CNS (n = 1). The response rate was 60% (95% confidence interval, 30% to 90%). One complete response was achieved, in addition to five partial responses, two cases of stable disease, and two cases of progressive disease. All patients with bone marrow involvement achieved complete clearance of tumor cells. The patient with CNS disease had progressive disease. All patients had severe hematopoietic toxicity (grade 4 neutropenia and grade 3/4 thrombocytopenia after most cycles). Other toxicities included grade 2 diarrhea in 30%. No echocardiographic changes were detected. CONCLUSION: Idarubicin is active in extraocular retinoblastoma. The activity of this drug should be explored in future phase III studies.

scholarly journals An Integrated Safety Summary of Omadacycline, a Novel Aminomethylcycline Antibiotic

2019 ◽  
Vol 69 (Supplement_1) ◽  
pp. S40-S47 ◽  
Author(s):  
Steven Opal ◽  
Thomas M File ◽  
Tom van der Poll ◽  
Evan Tzanis ◽  
Surya Chitra ◽  
...  
Keyword(s):  
Bacterial Pneumonia ◽  
Bone Growth ◽  
Package Insert ◽  
Late Pregnancy ◽  
Phase Iii ◽  
Tooth Discoloration ◽  
Phase Iii Study ◽  
Clinical Trial Results ◽  
Muscarinic M2 Receptors ◽  
Phase Iii Studies

AbstractOmadacycline is a semisynthetic tetracycline antibiotic. Phase III clinical trial results have shown that omadacycline has an acceptable safety profile in the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Similar to most tetracyclines, transient nausea and vomiting and low-magnitude increases in liver aminotransferases were the most frequent treatment-emergent adverse events in phase III studies but were not treatment limiting. Package insert warnings and precautions for omadacycline include tooth discoloration; enamel hypoplasia; inhibition of bone growth following use in late pregnancy, infancy, or childhood up to 8 years of age; an imbalance in mortality (2%, compared with 1% in moxifloxacin-treated patients) was observed in the phase III study in patients with community-acquired bacterial pneumonia. Omadacycline has no effect on the QT interval, and its affinity for muscarinic M2 receptors resulted in transient heart rate increases following dosing.

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