Purpose To compare the efficacy and toxicity of pemetrexed versus docetaxel in patients with advanced non—small-cell lung cancer (NSCLC) previously treated with chemotherapy. Patients and Methods Eligible patients had a performance status 0 to 2, previous treatment with one prior chemotherapy regimen for advanced NSCLC, and adequate organ function. Patients received pemetrexed 500 mg/m2 intravenously (IV) day 1 with vitamin B12, folic acid, and dexamethasone or docetaxel 75 mg/m2 IV day 1 with dexamethasone every 21 days. The primary end point was overall survival. Results Five hundred seventy-one patients were randomly assigned. Overall response rates were 9.1% and 8.8% (analysis of variance P = .105) for pemetrexed and docetaxel, respectively. Median progression-free survival was 2.9 months for each arm, and median survival time was 8.3 versus 7.9 months (P = not significant) for pemetrexed and docetaxel, respectively. The 1-year survival rate for each arm was 29.7%. Patients receiving docetaxel were mo...

https://ascopubs.org/doi/pdf/10.1200/JCO.2004.08.163

Randomized Phase III Trial of Pemetrexed Versus Docetaxel in Patients With Non–Small-Cell Lung Cancer Previously Treated With Chemotherapy

The CONSORT (Consolidated Standards of Reporting Trials) Statement, including a checklist and a flow diagram, was developed to help authors improve their reporting of randomized controlled trials. Its primary focus was on individually randomized trials with 2 parallel groups that assess the possible superiority of one treatment compared with another but is now being extended to other trial designs. Noninferiority and equivalence trials have methodological features that differ from superiority trials and present particular difficulties in design, conduct, analysis, and interpretation. Although the rationale for such trials occurs frequently, those designed and described specifically as noninferiority or equivalence trials appear less commonly in the medical literature. The quality of reporting of those that are published is often inadequate. In this article, we present an adapted CONSORT checklist for reporting noninferiority and equivalence trials and provide illustrative examples and explanations for those items amended from the original CONSORT checklist. The intent is to improve reporting of noninferiority and equivalence trials, enabling readers to assess the validity of their results and conclusions.

/pdf/reporting-of-noninferiority-and-equivalence-randomized-v12srq216e.pdf

Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement.

The field of interventional oncology with use of image-guided tumor ablation requires standardization of terminology and reporting criteria to facilitate effective communication of ideas and appropriate comparison between treatments that use different technologies, such as chemical (ethanol or acetic acid) ablation, and thermal therapies, such as radiofrequency, laser, microwave, ultrasound, and cryoablation. This document provides a framework that will hopefully facilitate the clearest communication between investigators and will provide the greatest flexibility in comparison between the many new, exciting, and emerging technologies. An appropriate vehicle for reporting the various aspects of image-guided ablation therapy, including classification of therapies and procedure terms, appropriate descriptors of imaging guidance, and terminology to define imaging and pathologic findings, are outlined. Methods for standardizing the reporting of follow-up findings and complications and other important aspects that require attention when reporting clinical results are addressed. It is the group's intention that adherence to the recommendations will facilitate achievement of the group's main objective: improved precision and communication in this field that lead to more accurate comparison of technologies and results and, ultimately, to improved patient outcomes.

https://radiologie-uni-frankfurt.de/sites/radiologieinstitut/content/e4864/e299/e1255/e10384/Goldberg_Image-guidedtumorablation_standardizationofterminology_ger.pdf

Image-guided Tumor Ablation: Standardization of Terminology and Reporting Criteria

Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial

ContextThe direct thrombin inhibitor bivalirudin has been associated with better
efficacy and less bleeding than heparin during coronary balloon angioplasty
but has not been widely tested during contemporary percutaneous coronary intervention
(PCI).ObjectiveTo determine the efficacy of bivalirudin, with glycoprotein IIb/IIIa
(Gp IIb/IIIa) inhibition on a provisional basis for complications during PCI,
compared with heparin plus planned Gp IIb/IIIa blockade with regard to protection
from periprocedural ischemic and hemorrhagic complications.Design, Setting, and ParticipantsThe Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical
Events (REPLACE)–2 trial, a randomized, double-blind, active-controlled
trial conducted among 6010 patients undergoing urgent or elective PCI at 233
community or referral hospitals in 9 countries from October 2001 through August
2002.InterventionsPatients were randomly assigned to receive intravenous bivalirudin (0.75-mg/kg
bolus plus 1.75 mg/kg per hour for the duration of PCI), with provisional
Gp IIb/IIIa inhibition (n = 2999), or heparin (65-U/kg bolus) with planned
Gp IIb/IIIa inhibition (abciximab or eptifibatide) (n = 3011). Both groups
received daily aspirin and a thienopyridine for at least 30 days after PCI.Main Outcome MeasuresThe primary composite end point was 30-day incidence of death, myocardial
infarction, urgent repeat revascularization, or in-hospital major bleeding;
the secondary composite end point was 30-day incidence of death, myocardial
infarction, or urgent repeat revascularization.ResultsProvisional Gp IIb/IIIa blockade was administered to 7.2% of patients
in the bivalirudin group. By 30 days, the primary composite end point had
occurred among 9.2% of patients in the bivalirudin group vs 10.0% of patients
in the heparin-plus-Gp IIb/IIIa group (odds ratio, 0.92; 95% confidence interval,
0.77-1.09; P = .32). The secondary composite end
point occurred in 7.6% of patients in the bivalirudin vs 7.1% of patients
in the heparin-plus-Gp IIb/IIIa groups (odds ratio, 1.09; 95% confidence interval
0.90-1.32; P = .40). Prespecified statistical criteria
for noninferiority to heparin plus Gp IIb/IIIa were satisfied for both end
points. In-hospital major bleeding rates were significantly reduced by bivalirudin
(2.4% vs 4.1%; P<.001).ConclusionsBivalirudin with provisional Gp IIb/IIIa blockade is statistically not
inferior to heparin plus planned Gp IIb/IIIa blockade during contemporary
PCI with regard to suppression of acute ischemic end points and is associated
with less bleeding.

https://jamanetwork.com/journals/jama/articlepdf/195991/joc22311.pdf

Bivalirudin and Provisional Glycoprotein IIb/IIIa Blockade Compared With Heparin and Planned Glycoprotein IIb/IIIa Blockade During Percutaneous Coronary Intervention: REPLACE-2 Randomized Trial

The recent revision of the Declaration of Helsinki and the existence of many new therapies that affect survival or serious morbidity, and that therefore cannot be denied patients, have generated increased interest in active-control trials, particularly those intended to show equivalence or non-inferiority to the active-control. A non-inferiority hypothesis has historically been formulated in terms of a fixed margin. This margin was historically designed to exclude a 'clinically meaningful difference', but has become recognized that the margin must also be no larger than the assured effect of the control in the new study. Depending on how this 'assured effect' is determined or estimated, the selected margin may be very small, leading to very large sample sizes, especially when there is an added requirement that a loss of some specified fraction of the assured effect must be ruled out. In cases where it is appropriate, this paper proposes non-inferiority analyses that do not involve a fixed margin, but can be described as a two confidence interval procedure that compares the 95 per cent two-sided CI for the difference between the treatment and the control to a confidence interval for the control effect (based on a meta-analysis of historical data comparing the control to placebo) that is chosen to preserve a study-wide type I error rate of about 0.025 (similar to the usual standard for a superiority trial) for testing for retention of a prespecified fraction of the control effect. The approach assumes that the estimate of the historical active-control effect size is applicable in the current study. If there is reason to believe that this effect size is diminished (for example, improved concomitant therapies) the estimate of this historical effect could be reduced appropriately. The statistical methodology for testing this non-inferiority hypothesis is developed for a hazard ratio (rather than an absolute difference between treatments, because a hazard ratio seems likely to be less population dependent than the absolute difference). In the case of oncology, the hazard ratio is the usual way of comparing treatments with respect to time to event (time to progression or survival) endpoints. The proportional hazards assumption is regarded as reasonable (approximately holding). The testing procedures proposed are conditionally equivalent to two confidence interval procedures that relax the conservatism of two 95 per cent confidence interval testing procedures and preserve the type I error rate at a one-sided 0.025 level. An application of this methodology to Xeloda, a recently approved drug for the treatment of metastatic colorectal cancers, is illustrated. Other methodologies are also described and assessed - including a point estimate procedure, a Bayesian procedure and two delta-method confidence interval procedures. Published in 2003 by John Wiley & Sons, Ltd.

Design and analysis of non-inferiority mortality trials in oncology

A fundamental assumption in the design and analysis of an active-control noninferiority trial is that the active control is truly effective. If this assumption does not hold, i.e., the active control is not effective, a harmful drug may be approved based on the result of a noninferiority trial. The assessment of the assumption is usually based on statistically significant results of historical randomized clinical trials on the active control, in which the conclusion may be falsely positive. This false positive rate, however, is not taken into consideration in current noninferiority trial test procedures. In this paper, various possible hypotheses for noninferiority trials are presented. The noninferiority hypotheses correctly associated with the objective of noninferiority trials are suggested. However, since there are no data collected for placebo in a noninferiority trial, this hypothesis cannot be directly tested by using data from noninferiority studies alone. The claim of noninferiority is b...

Hypotheses and Type I Error in Active-Control Noninferiority Trials

Purpose: The purpose is to describe the Food and Drug Administration (FDA) review and approval of imatinib (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) for treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in chronic phase. Experimental Design: The FDA reviewed data in electronic format from a randomized controlled clinical trial of 1106 adult patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase, comparing imatinib with the combination of IFN- and cytarabine. Results: Imatinib showed clinically and statistically significantly better results for time-to-progression to accelerated phase or blast crisis, progression-free survival, complete hematological response rate, and cytogenetic response rate. With a median follow-up of 14 months, a maximum follow-up of 19.5 months, and an expected median survival of 5– 6 years on the IFN-/cytarabine control arm, few of the expected progressions to accelerated or blast phase or deaths have occurred. Imatinib was also better tolerated. Edema, nausea, rigors, neutropenia, and headache were more frequent in women. Only 57% of the IFN- target dose was administered, and only 68% of patients received any cytarabine. However, this does not appear to adequately explain the superiority of imatinib observed in this trial. Results of a population pharmacokinetic study in a subgroup of 371 patients and a separate rifampin-imatinib drug-drug interaction study in healthy volunteers are presented. Conclusions: On December 20, 2002, imatinib was granted accelerated approval under subpart H, rather than regular approval. Follow-up is short compared with the natural history of chronic phase CML or more mature results with established therapies such as IFN- or transplantation. If imatinib should stop working after 1.5–2 years, the results could be importantly different from the present analysis. As a Phase IV postmarketing commitment, the applicant has agreed to provide follow-up reports on this imatinib study annually for the next 6 years.

Report from the FDA Approval Summary: Imatinib Mesylate Capsules for Treatment of Adult Patients with Newly Diagnosed Philadelphia Chromosome- positive Chronic Myelogenous Leukemia in Chronic Phase

Gang Chen

Papers

Design and analysis of non-inferiority mortality trials in oncology

Hypotheses and Type I Error in Active-Control Noninferiority Trials

Report from the FDA Approval Summary: Imatinib Mesylate Capsules for Treatment of Adult Patients with Newly Diagnosed Philadelphia Chromosome- positive Chronic Myelogenous Leukemia in Chronic Phase

Some statistical issues of relevance to confirmatory trials

Active Control Trials