Master Protocols: New Considerations in Cancer Trial Design

Cancer research is gaining momentum, especially in the field of gene-targeted therapies.

On the other hand, traditional trial designs fail to tackle the complexity of approving new cancer therapies. Luckily, new trial designs are emerging that seem to correspond to advancements in genomic sequencing of tumors.

So far, these new approaches have accounted for the increased trial feasibility, more accurate assessments of new therapies, and have significantly accelerated drug approval paths.

Here, we will reveal the essence of these new trial designs that tend to overpass the traditional trial concepts. But first, we’ll introduce the controversy in cancer studies that are driving these trends.

The New Momentum in Cancer Research

Genetic sequencing has sprung on a new era in medical research, with cancer being the prime targeted disease type.

Namely, the ability to differentiate cancers by their genetic mutations, has fueled the development of “precision oncology,” also known as targeted treatments.

Targeted therapy implies the use of medications according to a patient’s genetic mutation. It is generally perceived as more effective and less harmful and is becoming the more desirable treatment option for pharmaceutical companies and patients alike.

However, this momentous scientific achievement has created a particular challenge for clinical trials – the inability to investigate the multitude of genetic sub-populations in traditional trial design.

When investigating patient groups with the same tumor types (for example, prostate, gastric, lung, breast, or colorectal), we can determine and classify patients according to a molecular subtype of the tumor. The genetic mutation of a cancer-type determines each molecular subtype, thus the patients can be further divided into analogous sub-groups.

Considering the subgroups’ heterogeneity, it is virtually impossible to conduct phase I-III clinical trials according to each subpopulation while using a standard trial design.

The Main Disadvantages of Traditional Trial Designs

In traditional trials, patients are classified by their primary cancer and stage, and randomized controlled trials are conducted for each patient population to create standard therapies.

Molecularly targeted agents attack cancer cells selectively or induce the specific immune response to molecularly unique cellular transformations. This means that a single randomized group of patients can not account for the many variables needed to thoroughly investigate the therapy’s effectiveness.

The main obstacles a classical trial design has are:

  • Inter- and intra-patient heterogeneity. In fact, patients with the same tumor types can exhibit different treatment responses, depending on the patient characteristics or disease stage. Even within the same patient, differences in the nature of cancer cells within the tumor tissue can generate a different treatment response.
  • Differences in cellular signaling pathways. Some gene mutations generate different cellular activity and interfere with paracrine intercellular communication.
  • Differences in response to the treatment itself. Acting with different targeting agents on different subpopulations is needed in order to differentiate the therapy effectiveness correctly.

The problem with traditional trial designs in genetically sequenced tumor trials is that in order to function, one must obtain a homogenous population of patients. Although ideal, this scenario is less likely to occur, given that it takes time to recruit patients with low levels of inter-individual genetic variations of the tumor.

Additionally, traditional trial designs might appear incapable of tracking the designated biomarker, thus often need trial adaptation at some point.

Standard protocols need to be expanded to a framework of multiple sub-studies that attack single or multiple tumor types.

These diversified trial designs are called Master Protocols and are becoming the illuminating point in novelty cancer drug research.

What are Master Protocols?

Master protocols are trial designs that propose a framework for the investigation of multiple sub-populations, created according to molecular subtypes, disease types, and therapeutic agents. They are becoming more popular in clinical trials that investigate targeted anti-cancer therapies.

Master protocols define a trial infrastructure that can be differentiated into multiple parallel sub-studies and provide better solutions for patient recruitment and the collection, analysis, and management of data.

There are several approaches to creating a master protocol, and they are defined as Umbrella trials, Basket trials, and Platform trials.

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