Literature search
The study selection process is presented in Appendix Figure 1. We identified 5869 abstracts from our database searches, with an additional 140 records 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 only available through trial registries, with three trials in the pre-recruitment phase (NCT03339843, NCT03915678, and NCT03872427). A complete list of trials, with corresponding citations, is provided in Appendix Tables 6-8. In summary, we identified 49 basket trials, 18 umbrella trials, and 16 platform trials.
Trends of master protocols
There has been a rapid increase in the number of master protocols published in the last five years (Figure 2). From our literature search, we identified nine completed and published master protocol trials, including results. The Imatinib Target Exploration Consortium Study B2225 [16, 17], a basket trial, was the first master protocol to be conducted in 2001. This was followed by the platform trial STAMPEDE, that was first proposed in 2005 [8, 9, 18-28]. We identified 68 ongoing master protocols (39 basket trials, 17 umbrella trials, and 12 platform trials) recruiting patients; of these, 11 basket trials [29-38], eight umbrella trials [39-46], and four platform trials [24, 47-50] have published results (Appendix Table 10).
At the time of writing (August 1st, 2019), one platform trial (LEAP; NCT03092674) is currently suspended for an unscheduled safety data review [51]. EBOLA (NCT02380625), a platform trial supported by the Bill and Melinda Gates Foundation in response to the 2014 West Africa Ebola outbreak, has been terminated, as it could not be launched in time in response to the outbreak [52].
Trial characteristics of master protocols
Trial characteristics of the master protocols are presented in Appendix Table 9, and the sample size distribution of these master protocols displayed as box plots is provided in Figure 3.
The majority of master protocols were basket designs, with 49 identified in the current review. Among basket trials, all except for one trial involved a drug investigation (n = 48/49); NCT03003195 was the exception as a proposed vaccine basket trial. The majority of basket trials were exploratory (i.e. phase I or phase II; n = 47/49) and were not blinded, including of their outcome assessors (i.e. open-label; n = 46/49); almost half of the included basket trials only investigated a single intervention arm (n = 28/48; one did not report information on the number of interventions), with the majority not involving a control group or randomization (n = 44/49). The median sample size of basket trials was 205 participants (Interquartile range, Q3-Q1 [IQR]: 500-90=410), with a median study duration of 22.3 (IQR: 74.1-42.9=31.1) months. ALCHEMIST (NCT02193282; NCT02595944; NCT02201992) and CLUSTER (NCT02059291) [57-59] were the only phase III basket trials, which were comprised of three interventions arms and were of an open-label design.
Eighteen umbrella trials were identified. All umbrella trials investigated experimental drugs, with eight out of the 18 trials having used randomization to assign patients into different arms. The median sample size of umbrella trials was 346 participants (IQR: 565-252=313), with a median study duration of 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 also exploratory (n = 16/18;) and open-label (n = 16/17; one did not report information on blinding).
Our review returned 16 platform trials. All of the platform trials involved investigation of experimental drugs. The median sample size was 892 (IQR: 1835-255=1580), with median study duration of 58.9 (IQR: 101.3-36.9=64.4) months. Nearly all platform trials were of open-label design (n = 12/14; two trials did not report information on blinding), similar to basket and umbrella trials. In contrast to basket and umbrella trials, however, phase III investigation was more common among platform trials (n = 7/15; one did not report information on phase); four of these 7 platform trials were seamless II/III trials. In the majority of platform trials, patients were assigned by randomization (n = 15/16). PRISM (NCT03527147) was the only non-randomized platform trial, though this is currently a phase I study. However, the trial registry of PRISM indicates that future arms may be added. In STAMPEDE [8, 9, 18-28] and I-SPY2 [49, 50, 53, 60-64], several agents have graduated from the phase II evaluation with seamless transitions into phase III evaluations. The phase III evaluation for the I-SPY program is called I-SPY3.
Disease characteristics of master protocols
The patient and disease characteristics of master protocols are provided in Appendix Table 10. Most studies were in adult populations (n = 69/83), with nearly all in the field of oncology (n = 76/83). No umbrella trials were conducted outside of oncology. Notably, two basket trials were conducted for other clinical indications, namely hereditary periodic fevers (CLUSTER; NCT02059291) [57-59] and complement-mediated disorders (TNT0009 Basket trial). Additionally, five platform trials have been designed for influenza (ALIC4E; ISRCTN27908921) [65], Ebola (EBOLA) [52], pneumonia (REMAP-CAP; NCT02735707), pre-operative surgery (UPMC REMAP; NCT03861767) and Alzheimer’s disease (The DIAN-TU platform; NCT01760005) [48].
Geographic representation of master protocols
The information on the geographical representation of the current master protocols are provided in Appendix Table 11. The majority of current master protocols have taken place in the United States (n = 44/83) (Figure 4). Other high-income countries such as the UK (n = 25), France (n = 23), Spain (n = 17), and Canada (n = 13) were the next most common countries. There were no master protocols observed from low-income countries, though the EBOLA (NCT02380625) trial had been proposed for Guinea, Sierra Leone, and Liberia [52]. Two upper-middle-income countries, Brazil and Mexico, were involved in the DIAN-TU platform trial (NCT01760005), but these countries only accounted for three of 36 study sites [48]. China, an upper-middle income country, has centres participating in FUTURE (NCT03805399), GBM AGILE [47, 53, 54], TRUMP (NCT03574402), and VE-BASKET (NCT01524978) [55, 56] trials, but it should be noted that in China only accounts for a minority of study sites in GBM AGILE and VE-BASKET.