The US FDA recommends efficient clinical trial design strategies to expedite the development of oncology drugs and biologics. FDA also provides guidance and advice to sponsors of drugs and biologics for cancer treatment regarding the design and conduct of clinical trials, other than first-in-human (FIH) trials.

In contrast to traditional trial designs, where a single drug is tested in a single disease population in one clinical trial, master protocols use a single infrastructure, trial design, and protocol to simultaneously evaluate multiple drugs and/or disease populations in multiple substudies, allowing for efficient and accelerated drug development.

In the previous article, we have discussed the RCT and adaptive clinical trial designs. In the current article, we will be discussing modern trial designs such as basket (bucket), umbrella &. platform trial designs which are recommended and most efficient trial designs.

Before going into the details of various trial designs such as basket trials, umbrella trials, or platform trial designs lets understand a master protocol.

What is the master protocol?

A master protocol is defined as a study protocol designed with multiple substudies, which may have different objectives and involves coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes within the overall trial structure.

The sponsor may design the master protocol with either a fixed or adaptive design with an intent to modify the protocol to incorporate or terminate individual substudies within the master protocol.

These master protocols offer unique and flexible designs and can incorporate therapies with different mechanisms of action, biomarker development, and genetic subtyping.



What are the novel master trial designs?

Master protocols, classified as basket trials, umbrella trials, and platform trials, are novel designs that investigate multiple hypotheses through concurrent sub-studies (e.g., multiple treatments or populations or that allow adding/removing arms during the trial), offering enhanced efficiency and a more ethical approach to trial evaluation.

These designs are mostly used in Oncology trials but however can be used in other disease trials.

Despite the many advantages of these designs and the FDA recommendation for using such designs, many researchers tend to still use traditional designs due to a lack of knowledge or a well-established strategy in clinical drug development.

Basket trial designs (Bucket trials)

A type of clinical trial design that tests how well a new drug or other substance works in patients who have different types of cancer that all have the same mutation or biomarker.

Traditionally clinical trials would focus on the treatment of cancers for some specific genetic mutation or at certain locations such as lung, breast, etc. A more recent development for oncology clinical trials such as a basket study includes patients with a certain genetic mutation in common regardless of the site of origin of cancer in the body. Basket studies are sometimes referred to as bucket studies.

For example, patients recruited in the basket study have the same genetic mutation but cancers located in different regions such as lung, liver, prostate, etc. 

Basket trials can be relatively simple in design to include specific treatment arms or ‘baskets’ for cancers of different origins or locations. The design can also become more complex with the baskets including more than 1 genetic mutation across multiple cancer locations or they may be designed to evaluate multiple drugs across a selected number of genetic mutations, and cancer locations.

Advantages of basket trials

  • Basket studies can be useful to determine if a drug targeting genetic mutation at a particular site may be effective in treating that same genetic mutation found in cancer located in another site of the body.
  • These designs help to evaluate if a drug would be good candidates for larger trials with a more specific target, in terms of origin or location of cancer.
  • The US FDA considers a basket study to be adequate evidence for approval and recommends for the researcher to utilize such trial designs.
  • For already approved drugs, treating cancer with a specific genetic mutation at one location, a basket study can be useful to see if the efficacy translates to cancer at other locations in the body as only one genetic assay is required for screening patients for study enrollment.
  • Exposure in multiple contexts can provide an additional understanding of the mechanism of sensitivity and resistance.

Drawbacks

  • Some baskets may have small sample sizes if the mutation is rare
  • Without a comparative arm, can’t distinguish predictive from prognostic.
  • Single-arm sub-studies generally require a tumor response rate endpoint.
  • Challenging to define historical controls across diseases.

Basket trial experiences

A basket study was conducted involving patients with BRAF genetic mutation, and it was determined that vemurafenib was also effective in treating a rare blood cancer known as Erdheim-Chester Disease (ECD), where patients have BRAF V600 genetic mutation. This basket study helped lead to the eventual FDA approval for vemurafenib to treat BRAF ECD in 2017

Basket trials patterns

Umbrella trial designs

In umbrella trials, patients are enrolled with one cancer type but with different genetic changes within each tumor and consists of many small sub-trials to test multiple drugs simultaneously in one large trial.

  • Patients receive different targeting treatments matched to their genetic aberration. 
  • The term “umbrella” refers to the separation of one alleged cancer into many sub-cancers depending on their molecular features.
  • Sub-studies may be single-arm, phase II, or phase II/III trials that are randomized and compared to placebo or standard therapy. 
  • There is also a “default arm” which assigns patients without a specific marker to receive the standard treatment
  • Umbrella trials are often single-arm or randomized sub-studies that are confirmatory.

Umbrella trial experiences

In Lung-MAP Patients with previously-treated advanced squamous cell lung cancer. Initially 3 parallel randomized phase II/III sub-trials for targeted therapy vs. SOC (docetaxel) with the goal of 500-1,000 patients screened per year and Contains 4th cohort: non-match study for patients not eligible for target cohorts.

Advantages

  • The umbrella trials in oncology offer a new trial design aiming to test different types of treatments in an innovative and effective way.
  • The risk for participants is minimized, expected benefits are maximized; and 
  • The possible benefits to participants and society outweigh or are proportional to the risks associated with participation in the study. 

Drawbacks of umbrella trials

  • Require larger size, particularly when sub-trials are randomized
  • Longer duration
  • Difficulty enrolling rare molecular subtypes of a single tumor type
  • Susceptibility to changes in the “treatment landscape” during the trial

Umbrella trial design patterns

Super umbrella trials

The combination of the bucket trials and the umbrella trials creates the “Super Umbrella Trials”

Platform trials

Platform trials, also referred to as Multi-Arm, Multi-Stage (MAMS) design trials are trials that evaluate several interventions against a common control group and can be perpetual and further accept additions or exclusions of new therapies or patient populations during the trial. 

  • Basket and umbrella trials could also be considered platform trials if they permit the addition or exclusion of new treatments during the trial.
  • In a platform trial, interim analyses evaluate the efficacy or futility of each targeted therapy, and their results are used to add new ones or to.exclude certain targeted therapies

Advantages

  • Platform trials permit relatively flexible addition or exclusion of treatment methods or patient populations, thereby enabling an efficient transition to a confirmatory trial.
  • Do not require a new trial infrastructure for every treatment under investigation and It allows the sharing control group means less recruitment of patients is required.

Drawbacks

  • Challenges of the platform trial include its large-scale, long-term nature, high costs of managing and executing the trial, and
  • Needs to build organizations or frameworks that can operate these trials perpetually.

Other than the above-mentioned trials, there are also other trial designs such as Seamless design where researchers combine the learning stage of Phase II trials and the confirmatory stage of Phase III trials and Internal pilot design where patients are few in number as in the case of rare diseases, allocating them to a pilot study rather than the definitive study could be seen as a wasteful approach.

However such trials are planned or designed during clinical strategy development in order to make an efficient design to overcome the hurdles that may come across while conducting trials and attaining valid clinical trial data.

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References

  1. https://med.stanford.edu/content/dam/sm/cisd/symposium-May2017-slides/EricPolley-May2017-symposium.pdf
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380524/
  3. https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-019-3664-1
  4. https://med.stanford.edu/content/dam/sm/cisd/symposium-May2017-slides/EricPolley-May2017-symposium.pdf
  5. https://www.pharmacytimes.com/contributor/ryan-chandanais-ms-cpht/2018/07/basket-studies-an-innovative-approach-for-oncology-trials