Saville BR, Berry SM. Efficiencies of platform clinical trials: A vision of the future. Clin Trials. 2016;13:358–66.

Eighteen umbrella trials were identified. All umbrella trials investigated experimental drugs, and eight out of the 18 trials used randomization to assign patients to different arms. The median sample size of umbrella trials was 346 participants (IQR: 565–252 = 313), and the median study duration was 60.9 (IQR: 81.3–46.9 = 34.4) months. The median number of interventions investigated in umbrella trials was 5 (IQR: 6–4 = 2). Similar to basket trials, the majority of umbrella trials were exploratory ( n = 16/18) and open-label (n = 16/17; one did not report information on blinding). Statistical designs of clinical studies are conventionally devised in consideration of distributions of test statistics that measure the extent of evidence acquired against a prespecified null hypothesis upon repeated sampling of the trial data for a given decision rule. For hypotheses of superiority, null hypotheses define value(s) of statistical parameters for which the underlying true state of nature is characterized by the absence of treatment effectiveness. For one-sample studies, the null often is represented by a fixed, prespecified value that represents an expected response rate considered inadequately low to justify additional investigation. Statistical designs of prospective clinical studies prespecify decision rules to be used as the basis for determining from the data the extent to which evidence against the null hypothesis confers its rejection. The decision rule determines the extent to which the trial’s conclusions could be explained as a result of chance. Marchetti A, Felicioni L, Malatesta S, et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol 2011;29: 3574- 3579 Research personnel recorded several group discussions of experienced executives in various operating companies of the Bell System who had completed the In‐Basket Test individually before the discussion period. From a content analysis of these discussions were derived a set of 11 scoring categories, each with a number of Bubtypes by which it was believed the responses of managers to the In‐Basket Test items could be described in a meaningful way. These inclUded such things as Activity Level, Type of Analysis reflected in the responses, Delegation, Consideration of Others, Decisiveness of Action, and the like. Comments of these and other executives who have taken the Business In‐Basket Teat have indicated that the task it presents is realistic and that managers feel personally involved in finding solutions to the problems raised by many of the itemsTol J, Nagtegaal ID, Punt CJA. BRAF mutation in metastatic colorectal cancer. N Engl J Med 2009;361: 98- 99 Chen A, Conley B, Hamilton S, Williams M, O’Dwyer P, Arteaga C, et al. NCI-Molecular Analysis for Therapy Choice (NCI-MATCH) trial: a novel public-private partnership. Eur J Cancer. 2016;69:S137. The study selection process is presented in Additional file 1: Figure S1. We identified 5869 abstracts from our database searches, and 140 more records were identified through hand searches of bibliographies and trial registries. Of these, 639 records were selected for full-text review. In total, 214 publications describing 83 trials met our inclusion criteria. Thirty-four trials were available only through trial registries, and three trials were in the pre-recruitment phase (NCT03339843, NCT03915678, and NCT03872427). A complete list of trials and the corresponding citations is provided in Additional file 1: Tables S6–S8. In summary, we identified 49 basket trials, 18 umbrella trials, and 16 platform trials. Trends of master protocols The term “master protocol” refers to a single overarching design developed to evaluate multiple hypotheses, and the general goals are improving efficiency and establishing uniformity through standardization of procedures in the development and evaluation of different interventions [ 5, 6]. Under a common infrastructure, the master protocol may be differentiated into multiple parallel sub-studies to include standardized trial operational structures, patient recruitment and selection, data collection, analysis, and management [ 3, 4, 5, 6]. We anticipate that the number of master protocols will continue to increase at a rapid pace over the upcoming decades. More efforts to improve awareness and training are needed to apply these innovative trial design methods to fields outside of oncology.

Progress in the areas of genomics, disease pathways, and drug discovery has advanced into clinical cancer research. The latest innovations in clinical trials have followed with master protocols, which are defined by inclusive eligibility criteria and devised to interrogate multiple therapies for a given tumor histology and/or multiple histologies for a given therapy under one protocol. 1, 2 The use of master protocols for oncology has become more common with the desire to improve the efficiency of clinical research and accelerate overall drug development. The LUNG-MAP study, for example, used a master protocol for a phase II/III comparative trial designed to evaluate biomarker-matched therapies in patients with previously treated advanced squamous non–small-cell lung cancer. 3 Shortly after initiation, the US Food and Drug Administration approved a new immunotherapy for the same population. The design’s flexibility facilitated subsequent modification of the standard of care, which preserved the relevance of the study. 1 A second example includes the CREATE study master protocol, which evaluated the efficacy of crizotinib in patients with ALK or MET mutations among six different tumor histologies, where each histology constituted a subtrial of ALK/MET-positive or ALK/MET-negative tumors. 2 Chen C, Li X, Yuan S, et al: Statistical design and considerations of a phase 3 basket trial for simultaneous investigation of multiple tumor types in one study. Stat Biopharm Res 8: 248- 257, 2016 Crossref, Google Scholar Three of four patients with anaplastic pleomorphic xanthoastrocytoma had partial responses. Responses were also observed in patients with the following tumor types: anaplastic thyroid cancer (two patients), cholangiocarcinoma (one patient), salivary-duct cancer (one patient), soft-tissue sarcoma (one patient), and ovarian cancer (one patient). In three of these patients (one each with anaplastic thyroid cancer, cholangiocarcinoma, and ovarian cancer), the responses have persisted for more than 12 months. Additional tumor regression that did not meet criteria for a response was observed in three patients with glioblastoma and one patient each with anaplastic ependymoma, pancreatic cancer, and carcinoma of unknown primary type. No patients with multiple myeloma have had a response to date. Safety Many types of response made by managers to In‐Basket Test items are consistent across items. (odd‐even reliability estimates are .80 or better for 24 out of 41 scores.) The singer used the force of his cash to have fabulous life-size models of R2-D2 and C-3PO created.

Trippa L, Alexander BM: Bayesian baskets: A novel design for biomarker-based clinical trials. J Clin Oncol 35: 681- 687, 2017 Link, Google Scholar Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18: 2095- 2103 Hyman DM, Puzanov I, Subbiah V, et al: Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med 373: 726- 736, 2015 Crossref, Medline, Google Scholar The bike is not quite as pristine as when he bought it. But he didn’t buy it to leave in some sort of trophy cabinet, he bought it to have a laugh with.”

Bateman RJ, Benzinger TL, Berry S, Clifford DB, Duggan C, Fagan AM, et al. The DIAN-TU Next Generation Alzheimer’s prevention trial: Adaptive design and disease progression model. Alzheimers Dement. 2017;13:8–19. The evidence presented supports the decision of the Appointment Commission to use AC methodology in the selection for positions in public office, and points to ways in which the process could be improved. To determine whether other malignancies with similar kinases respond to treatment, a single-arm, open-label, phase II study was conducted with inclusive enrollment across 40 different pathologic diagnoses. 24 Neither the number of indications was constrained nor the design devised to examine subpopulation-specific effects. The study pooled all indications for analysis. The study represents an example of the challenges posed by indication heterogeneity with conventional study design (eg, see Lacombe et al 25), the prediction of which may not be feasible in advance of a study’s implementation. Comparisons of the scores of middle‐management executives and management trainees revealed significant differences in a number of types of response to In‐Basket Test items. Trainees, for example, are more wordy than the experienced managers. They are less likely to take action on the basis of the importance of problems posed by the items and they see fewer implications for the organization as a whole in the various items in the test. Somewhat surprisingly, trainees more often make final decisions and take final action on items, while experienced executives seek additional information or see preliminary steps to be taken before final action can be accomplished. Both groups delegated tasks to subordinates to about the same extent, but the delegations of trainees tended to be complete while those of experienced executives contained some element of control in the form of procedures for making sure that the problem would be properly handled. Finally, the experienced executives more often went out of their way to be considerate both in special acts of consideration and in routine expressions of courtesy. Advances in genomics, disease pathways, and drug discovery have progressed into clinical cancer research. Innovations in trial design with basket trials facilitate interrogations of multiple therapies for a given tumor histology and/or multiple histologies for a given therapy-target combination that bridges aspects of translational and clinical research paradigms. We review basket trials and elucidate statistical considerations for implementation within exploratory and confirmatory settings.BRAF V600 mutations occur in various nonmelanoma cancers. We undertook a histology-independent phase 2 “basket” study of vemurafenib in BRAF V600 mutation–positive nonmelanoma cancers. Methods To the best of our knowledge, this is the first landscape analysis of master protocols. This was achieved through a methodologically robust and rigorous systematic literature review that included queries of medical literature databases, reference lists of included studies, and clinical trial registries. Unlike previous publications on master protocols that were limited in scope to select only specific studies, this review catalogues all master protocols that have been conducted or proposed to date. Of the 83 master protocols (49 basket trials, 18 umbrella trials, and 16 platform trials), the majority have involved investigation of experimental drugs in adult patients for the field of oncology. Rugo HS, Olopade OI, DeMichele A, Yau C, van’t Veer LJ, Buxton MB, et al. Adaptive Randomization of Veliparib-Carboplatin Treatment in Breast Cancer. N Engl J Med. 2016;375:23–34. Parker CC, James ND, Brawley CD, Clarke NW, Hoyle AP, Ali A, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392:2353–66.