Two-stage seamless transition design from open-label single-arm to randomized double-arm clinical trials

2016 ◽  
Vol 27 (1) ◽  
pp. 158-171 ◽  
Author(s):  
Haolun Shi ◽  
Guosheng Yin
Keyword(s):  
Clinical Trials ◽  
Sample Size ◽  
Phase Ii ◽  
Therapeutic Effects ◽  
Operating Characteristics ◽  
Phase Ii Trials ◽  
Open Label ◽  
Two Stage ◽  
Trade Offs ◽  
Experimental Drug

Conventional phase II clinical trials use either a single- or multi-arm comparison scheme to examine the therapeutic effects of the experimental drug. Both single- and multi-arm evaluations have their own merits; for example, single-arm phase II trials are easy to conduct and often require a smaller sample size, while multiarm trials are randomized and typically lead to a more objective comparison. To bridge the single- and double-arm schemes in one trial, we propose a two-stage design, in which the first stage takes a single-arm comparison of the experimental drug with the standard response rate (no concurrent treatment) and the second stage imposes a two-arm comparison by adding an active control arm. The design is calibrated using a new concept, the detectable treatment difference, to balance the trade-offs between futility termination, power, and sample size. We conduct extensive simulation studies to examine the operating characteristics of the proposed method and provide an illustrative example of our design.

scholarly journals Beyond p-values: A phase II dual-criterion design with statistical significance and clinical relevance

2018 ◽  
Vol 15 (5) ◽  
pp. 452-461 ◽  
Author(s):  
Satrajit Roychoudhury ◽  
Nicolas Scheuer ◽  
Beat Neuenschwander
Keyword(s):  
Sample Size ◽  
Phase Ii ◽  
Clinical Relevance ◽  
Statistical Significance ◽  
Effect Estimate ◽  
Type I ◽  
Operating Characteristics ◽  
Phase Ii Trials ◽  
Standard Design ◽  
Standard Designs

Background Well-designed phase II trials must have acceptable error rates relative to a pre-specified success criterion, usually a statistically significant p-value. Such standard designs may not always suffice from a clinical perspective because clinical relevance may call for more. For example, proof-of-concept in phase II often requires not only statistical significance but also a sufficiently large effect estimate. Purpose We propose dual-criterion designs to complement statistical significance with clinical relevance, discuss their methodology, and illustrate their implementation in phase II. Methods Clinical relevance requires the effect estimate to pass a clinically motivated threshold (the decision value (DV)). In contrast to standard designs, the required effect estimate is an explicit design input, whereas study power is implicit. The sample size for a dual-criterion design needs careful considerations of the study’s operating characteristics (type I error, power). Results Dual-criterion designs are discussed for a randomized controlled and a single-arm phase II trial, including decision criteria, sample size calculations, decisions under various data scenarios, and operating characteristics. The designs facilitate GO/NO-GO decisions due to their complementary statistical–clinical criterion. Limitations While conceptually simple, implementing a dual-criterion design needs care. The clinical DV must be elicited carefully in collaboration with clinicians, and understanding similarities and differences to a standard design is crucial. Conclusion To improve evidence-based decision-making, a formal yet transparent quantitative framework is important. Dual-criterion designs offer an appealing statistical–clinical compromise, which may be preferable to standard designs if evidence against the null hypothesis alone does not suffice for an efficacy claim.

Seamless phase II/III trial design with survival and PRO endpoints for treatment selection: Case study of RTOG 1216.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS6099-TPS6099
Author(s):  
David Ira Rosenthal ◽  
Qiang Zhang ◽  
Merrill S. Kies ◽  
Minh-Tam Truong ◽  
Richard Jordan ◽  
...  
Keyword(s):  
Sample Size ◽  
Phase Ii ◽  
Trial Design ◽  
Experimental Treatment ◽  
Phase Iii ◽  
Operating Characteristics ◽  
Phase Ii Trials ◽  
Trial Duration ◽  
Sequential Method ◽  
Common Control

TPS6099 Background: Clinical trial results from phase II trials to select an experimental treatment arm for separate phase III trial comparison can require years. Cancer clinical trials also now aim at both survival and PRO/functional outcomes, especially in head and neck (HN) studies. We developed a unique seamless phase II/III trial design to save on sample size and trial duration. The initial multi-arm phase II trial selects the most effective regimen among multiple experimental arms by first comparing each of the new treatments to a common control arm, using chosen endpoints, such as progression free survival. The winner will be tested for overall survival in the phase III study. Methods: We propose a phase II/III design to test the efficacy of experimental arms of postoperative radiation (RT) + docetaxel or RT + docetaxel + cetuximab in patients with HN squamous cancer. These are compared to the control arm of RT + cisplatin in the phase II part. Only one arm will be selected to go on to phase III depending on efficacy (PFS), PRO and safety outcomes. One experimental arm must be sufficiently better than the common control arm and the winner not having increased toxicity or functional cost to be selected for phase III inclusion. If not, the trial is halted for futility. Patients in the phase II selected arm and the control arm are included in phase III testing. Group sequential method is used to design each component. Separate interim efficacy and futility analyses are built in such that each endpoint can be monitored as in separate phase II, III trials. Once sample sizes are derived, operating characteristics for the seamless II/III design are evaluated through simulations under the null and various alternative hypotheses. Savings on sample size and time are compared to typical separate phase II and III designs and to the design testing only the arm of RT + docetaxel + cetuximab in phase II. Conclusion: The phase II/III RTOG 1216 HNC trial offers cost effectiveness, operational efficiency and scientific innovation.

Outcome of phase II oncology clinical trial abstracts presented at annual meeting of the American Society of Clinical Oncology (ASCO)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6010-6010 ◽  
Author(s):  
R. T. Hoeg ◽  
J. A. Lee ◽  
M. A. Mathiason ◽  
K. Rokkones ◽  
S. L. Serck ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Phase I ◽  
Sample Size ◽  
Annual Meeting ◽  
Phase Ii ◽  
Country Of Origin ◽  
Phase Ii Trials ◽  
Oncology Clinical Trials ◽  
American Society

6010 Background: Translation of evidence-based medicine into clinical practice depends on timely and full publication of clinical trials. Previous studies have shown that a substantial number of phase I and III trials presented at the annual meetings of ASCO remain unpublished more than 5 years after presentation. We investigated the outcome of phase II trials presented at ASCO. Methods: We searched for phase II trials using the 1997 ASCO Annual Meeting Proceedings. We excluded trials reporting only preliminary data or interim analyses. The following information were extracted from each study: type of presentation, country of origin, sample size, sponsor, treatment modality, novelty of treatment, and efficacy. A literature search was performed using the Medline and EMBASE databases up until January 2006 for full publications in peer-reviewed journals. If a trial was not found, the authors were contacted by E-mail. Results: We identified 124 phase II trials with 13.7%, 30.6%, and 55.6% presented orally, in poster, and in print, respectively. Most trials were either submitted from countries in North America (50.8%) or Europe (34.7%). Funding came from the pharmaceutical companies (24.2%), governments (20.2%), study institutions (15.3%), private foundations (9.7%), or was not specified (30.6%). The top 5 cancers studied were lung, breast, ovarian, gastric, and sarcoma. Treatment included mostly chemotherapy, either alone (87.1%) or in combination with other modalities (3.2%). To date only 70.2% of the trials have been published. The median time to publication for all abstracts was 23 months. The cumulative rates of publication were 12.9%, 34.7%, 51.6%, 64.5%, and 68.5% at 1, 2, 3, 5, and 7 years, respectively. None of the factors we analyzed, including type of presentation, country of origin, sample size, sponsor, novelty of treatment, and efficacy, influenced the likelihood of or time to publication. Conclusions: About a third of phase II oncology clinical trials initially presented as abstracts at the 1997 ASCO annual meeting have not been published almost a decade later. Similar to phase I and III trials, underreporting of phase II trials is an important problem with serious implications for clinical practice that needs to be addressed. No significant financial relationships to disclose.

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