Multi-Arm Multi-Stage (MAMS)

Overview

In summary:

Multi-arm multi-stage (MAMS) trials evaluate several active treatments (e.g., different regimens or doses/schedules of the same treatment or completely different treatments) in a single trial;
Treatment arms that show promise on the basis of accrued outcome data are retained for further testing, whilst those unlikely to show benefit are dropped;
The criteria for selecting or dropping arms at interim analyses should be pre-specified;
MAMS designs are useful where multiple competing treatments need to be reduced to a small number of most promising ones.

Video

Concept behind the MAMS design

Motivation

MAMS clinical trials compare several active treatment arms, often to a single, shared control arm. MAMS trials use one or several interim analyses to assess whether some treatments:

are promising but need further evaluation to ascertain evidence (trial can be stopped completely if none of the treatments is promising);
appear unlikely to work and can be discontinued (also known as futility, where the accumulating data suggest a low chance of benefit; “not worth pursuing a lost cause”);
show overwhelming evidence of an effect and can be discontinued for clear clinical benefit.

These trials are efficient as they share comparator groups (e.g., the control group if there is one) in a single trial rather than running a series of separate two-arm trials. This means multiple research questions can be addressed in a single trial that directly compares the treatment arms to each other. In addition, poorly performing arms are dropped quickly from the study – thus shifting research resources (and participants) away from less promising interventions and onto those that are suggesting more benefit (see¹^,²^,³). Arguably these trials are more ethical since ineffective or potentially unsafe treatments are stopped early and the chances of a patient being allocated to study treatments are usually higher than the control. MAMS designs can also address multiple research objectives across trial phases (e.g., learning and confirmatory) in one trial under one protocol without discontinuing the trial between phases - thus speeding the evaluation of new treatments (see trial phases covered by MAMS designs).

MAMS designs can be extended to also add new treatment arms, a class of trials known as MAMS platform trials (see ⁴^,⁵). These trials are more complex and require additional practical and statistical considerations that are discussed in the literature (e.g., ⁴^,⁵^,⁶^,⁷^,⁸^,⁹).

References

1. Jaki et al. Multi-arm multi-stage trials can improve the efficiency of finding effective treatments for stroke : a case study and review of the literature. BMC Cardiovasc Disord. 2018;18:215.
2. Jaki. Multi-arm clinical trials with treatment selection: what can be gained and at what price? Clin Investig. 2015;5:393–9.
3. Millen et al. Adaptive trial designs: what are multiarm, multistage trials? Arch Dis Child Educ Pract Ed. 2019;0:1-3.
4. Angus et al. Adaptive platform trials: definition, design, conduct and reporting considerations. Nat Rev Drug Discov. 2019;18:797–807.
5. Parmar et al. Testing many treatments within a single protocol over 10 years at MRC Clinical Trials Unit at UCL: Multi-arm, multi-stage platform, umbrella and basket protocols. Clin Trials. 2017;14:451–61.
6. Choodari-Oskooei et al. Adding new experimental arms to randomised clinical trials: Impact on error rates. Clin Trials. 2020;17:273–84.
7. Schiavone et al. This is a platform alteration: A trial management perspective on the operational aspects of adaptive and platform and umbrella protocols. Trials. 2019;20:264.
8. Hague et al. Changing platforms without stopping the train: experiences of data management and data management systems when adapting platform protocols by adding and closing comparisons. Trials. 2019;20:294.
9. Lee et al. Statistical consideration when adding new arms to ongoing clinical trials: the potentials and the caveats. Trials. 2021;22(1):203.