Cat Hall, VP Data and Quality, Endpoint Clinical 

Master protocols – single trials that explore the therapeutic effect of one or more agents with multiple hypotheses through a series of sub-studies – are meant to speed life-saving therapies to market. Because they use a common system for patient selection, logistics, templates, and data management, they offer process efficiencies over a series of individual trials. McKinsey estimates that using a master protocol cuts 12 to 15 percent out of the trial budget and shaves about 13 to 18 percent from the study timeline.

 The structure of a master protocol is particularly useful in the study of complex diseases such as oncology and in challenging rare diseases.

Yet, for all their advantages, master protocols are not only difficult to design, but also to support from a technological standpoint. The interactive response technology (IRT) must be built to accommodate randomization, drug assignment, and supply management as the protocol evolves over the course of what can easily be a decade or more of development efforts.

IRTs that support master protocols must be configured to meet future requirements that are, in many respects, unknowable. So, the requirements gathering step is especially daunting; it’s a little like answering the question, “How long is a piece of string?” The process is an exercise in thinking ahead, anticipating all possibilities, and remaining flexible. The goal is to preclude the need to reconfigure the system in fundamental ways at a future date. The best approach is to:

Begin thinking through the system requirements with the IRT vendor at least six weeks in advance. Building the IRT for a master protocol is inherently more complex than for a single study and naturally will take more time.

Approach the challenge holistically with the help of a cross-functional team that includes all eClinical partners.

Define what elements of the protocol will be variable, and which will remain static. For example, a core set of questions used to screen patients may remain the same across all sub-studies and for the life of the protocol. Dosing, on the other hand, might be quite variable.

Then, for each identified variable, establish the outer limits of the range. Dosing, for example, might be confined to 10 – 100 mg. (This step, of course, dovetails with the creation of the statistical analysis plan.)

Determine, in consultation with the IRT supplier, the basic “rules” that will govern randomization. Will patients be able to move between studies? How will patients who are eligible for more than one study be assigned?

Again, discuss with the IRT partner the most efficient way to supply the investigational and comparator products across the sub-studies. Is if feasible to pool supplies, or must each study have its own resupply algorithm?

It is important to work with an IRT partner who has an established track record for quality, as it is for any trial. Specifically for master protocols, the IRT vendor should, ideally, also:

Offer an extremely flexible system, one can be configured within the established parameters.

Deliver extensive control for administrative functions to the sponsor. The sponsor might, for instance, be given the ability to manage cohorts, including setting up new cohorts, deciding how many patients will be randomized to each, establishing the criteria and dosing.

Demonstrate both longevity and a willingness to maintain the platform over time.

Operate collaboratively and work well with multiple other vendors.

While it is challenging to design an IRT to support a master protocol, it is nonetheless do-able with a team prepared to devote considerable forethought, planning, and coordination to the solution.

Lesser, N., Naaz, B., “Master Protocols: Shifting the Drug Development Paradigm,” Deloitte Insights, Sept. 17, 2018. 

https://www2.deloitte.com/us/en/insights/industry/life-sciences/master-protocol-clinical-trial-drug-development-process.html

Cat Hall, VP Data and Quality, Endpoint Clinical

Articles

Master Protocols Demand a Master Plan for the IRT: Success Tied to Forethought, Flexibility, and Coordination