In this chapter, we review the history of clinical trials. We review the famous 1948 streptomycin trial for tuberculosis to highlight how the discipline of randomised clinical trials was born out of economic hardship. Other historical events of adaptive trial designs and master protocols are discussed in this chapter.

In this chpater, we review the standards and guidelines for adaptive trial designs and master protocols. Methodological rigour and transparent reporting are required in all clinical trials. Adaptive trial designs and master protocols are no exception. The standard reporting guidelines and risk-of-bias assessments for conventional trials can be applied to adaptive trial designs and master protocols. Adaptive trial designs have pre-planned adaptations and analysis plans that are specified in a formal way that outline how the data will be used to guide the design. Planning of adaptive clinical trials, basket trials, umbrella trials, and platform trials will require early engagement with the stakeholders and methodologists to think through potential hurdles and challenges of the statistical design and its implementation.

In this chapter, we review practical considerations for adaptive trial designs and master protocols. Planning adaptive trial designs and master protocols require resources and time. It is best to plan ahead with key stakeholders with statistical, content, and operational expertise to make the trial possible. Customised education and training plans will likely be required for the vendors, investigators, and other personnel involved in the trial. Critical thinking is needed from the personnel involved to create flexible technology systems and procedures required to execute these clinical trials. During the conduct, it is important to document what happened, maintain a proper firewall, and manage external communications effectively. For long-term platform trials, study adjustments may be unavoidable, but it is important that these adjustments are made before the patients are enrolled into the new study arm.

In this chapter, we discuss the key concepts, terminologies, and principles of master protocols. The term ‘master protocol’ is often misunderstood and misused. This term refers to a single overarching protocol document that is developed with the intention of evaluating multiple interventional hypotheses. ‘Master protocol’ itself does not refer to a specific type of clinical trial. There are three types of clinical trials that are conducted using the master protocol framework: platform trials, basket trials, and umbrella trials. While master protocols can naturally extend to adaptive trial designs, the use of adaptive trial designs is not a defining feature of master protocols nor of platform, basket, and umbrella trials. Master protocols implement common screening, trial systems, and standardised operating procedures across multiple trial institutions under one centralised governance model. In addition to statistical efficiencies, operational efficiencies can be gained by adopting the master protocol framework.

This chapter introduces clinical research concepts and randomised clinical trials, covering the basics and building blocks that are necessary to understand the topics of adaptive trial designs and master protocols. Clinical trials are a type of prospective experimental studies in which human volunteers receive specific interventions according to the research protocol, then are followed longitudinally over time. Clinical trials are typically conducted in a sequence (from phase I, phase IIA, phase IIB, and phase III) that builds on knowledge accumulated from non-clinical and previous clinical studies. Randomisation is a process of random assignment of clinical trial participants to one or more intervention group(s) or control group under comparison. The use of randomisation provides a sound basis for making statistical causal inference when estimating the comparative treatment effects between groups. Fixed sample trial design refers to a type of designs where the trial data is only analysed once when a priori determined sample size has been reached. Fixed sample trial designs are designed with a fixed maximum sample size, a fixed number of interventions, and a defined end to the trial. This is the most common approach to clinical trial research.

In this chapter, we review ten common misconceptions of adaptive trial designs and master protocols encountered during our collective experience in teaching and working in the field of clinical trial research.