Newer Trial Designs

Clinical trials are vital to the discovery, development, and testing of new therapies. In the early years of oncology, clinical trials were conducted based on the cancer type and stage. Later on, we moved on to “enrichment’7” targeted” designs for the evaluation of clinical utility, choosing patient populations according to a single-molecular marker, such as epidermal growth factor receptor (EGFR) in head-and-neck squamous cell carcinoma, anaplastic lymphoma kinase (ALK) in nonsmall cell lung cancer (NSCLC), or human epidermal growth factor receptor 2 mutations in breast cancer. This helped to select the study populations in which each drug was more likely to be effective compared with an unselected population. To validate the clinical utility of a marker and determine if it is worth studying further, “Marker by Treatment Interaction” or “Marker-based Strategy” designs can be used ([Figs. 1 ]and [2]). In the marker by treatment-interaction design, the marker is measured in all patients, who are then stratified by their level of marker expression. In each group, the patients will be assigned different therapies to see if one treatment is superior to another. It is equivalent to doing two or more randomized controlled trials (RCTs) (e.g., two RCTs if the population is stratified into marker positive and marker negative groups). In the marker-based strategy design, after measuring the marker in all patients, they are randomized into two arms: In one, the treatment is decided according to marker status: standard therapy for marker-negative patients and experimental therapy for marker-positive patients. In the other arm, the treatment may be independent of marker status, with all receiving standard therapy or the patients may again be randomized to standard versus experimental therapy, irrespective of marker status. For a useful marker, the treatment outcomes in the marker-dependent treatment arm should be at least 30% better than in the marker-independent treatment arm.

Fig. 1 Marker x treatment interaction design.

Fig. 2 Marker strategy design.

At present, technological advances have enabled the characterization of tumors in ever greater detail, and consequently, we are faced with a higher number of precise targets against that new therapeutic interventions can be developed. It has even become possible to classify the tumors by molecular subtypes, regardless of their tissue of origin, such as the breast, colorectal, or lung. Since it would be impractical to design and conduct the separate clinical trials for each of these subpopulations, we now employ “master protocol” trial designs.

What is a “master protocol?” A master protocol is a single, overarching protocol, from which we can derive subprotocols for multiple substudies that run simultaneously. Each substudy targets a specific-molecular marker or therapy. Having a master protocol avoids wasting repetitive efforts on design, regulatory approval, and logistics planning for each trial. Master protocol trials can be “exploratory” phase I/II or “confirmatory” randomized phase III trials. Basket, umbrella, and platform designs are different kinds of master protocol trials, although each does not have a standardized definition. The advantage of master protocol trials is that they enable the concurrent testing of a wide range of markers, while overcoming heterogeneities in the patient population and reducing costs. One of the important drawbacks is a possible increase in false-positive findings due to concurrently running several small substudies.

Publication History

Article published online:
20 May 2021

• References

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