Monday, June 13, 2016

Basket (Bucket) Trial, Umbrella Trial, and Master Protocol

In response to the precision medicine or an old term ‘personalized medicine’, the clinical trial designs are also evolving in order. Over the last several years, two clinical trial designs have been proposed and implemented in many oncology trials: basket (or bucket) trials and umbrella trials.  The basket and umbrella trial designs are generally falling into the enrichment trial design with the purpose of avoiding over-treatment and saving valuable resources by matching the right drug to the right subgroup of patients through genetic biomarkers. While basket and umbrella trial designs are almost exclusively in oncology trials, we can assume that such designs can be generalized to therapeutics areas other than the oncology.

In general, here are the comparison of basket and umbrella trial designs with some example trials:

Basket (or Bucket) Trial
  Umbrella Trial
Targeted Therapy: biomarker analysis to identify patients likely to response
One Molecular Abnormality Targeted Across Multiple Tumor Types

Cancer is defined based on the genetic aberrant or biomarker signature (cancer with xxx positive biomarker)
One tumor type, multiple molecular targets

Cancer is defined as body location or histology (lung cancer, liver cancer,...)
Many diseases (or many cancer types), single subgroup, one drug
One disease (or one cancer type), multiple subgroups (identified by the biomarkers), many drugs
Test the effect of one or more drugs on one or more single mutations in a variety of cancer types
Test the impact of different drugs on different mutations in a single type of cancer
Biomarkers is usually measured locally
Biomarkers are usually measured centralized
Allows patients with multiple diseases and one or more target to be enrolled in cohorts or groups in one trial (the basket). This allows researchers to separately analyse the responses of patients as each tumour type can be put in one cohort, and assess the impact of the drug on all of the patients as one group. If one group shows a good response, we expand this group to immediately assess whether others could benefit from the new therapy. If another group does not show evidence of effectiveness, this group may be closed and the other cohort can continue the recruitment.
Designed to test the impact of different drugs on different mutations in a single type of cancer, on the basis of a centralised molecular portrait performed after obtaining informed consent: one disease, several molecular subtypes, several therapies. This design allows validation of a strategy based on a mixture of biomarkers and drugs
Cancers of different types are tested to see if they have a particular molecular abnormality. If they do, the patients with that abnormality are eligible to be treated with a new drug that targets that particular abnormality. The advantage of this approach is that it allows us to test new treatments across cancer types. On the other hand, we often have to test many patients to find that handful that have the abnormality targeted by the new treatment. If can be incredibly frustrating for a patient who agrees to be tested, only to be told he/she is not eligible to be treated on the study because his/her cancer does not have the appropriate target.
Patients with a given type of cancer are assigned a specific treatment arm based on the molecular makeup of their cancer. Umbrella trials have many different arms under the umbrella of a single trial.
Since the treatment assignment/stratification is based on molecular biomarkers, Umbrella trial requires the complicated process for centralized screening tests for multiple biomarkers. The genotyping to identify the molecular biomarkers, if done locally, could have results less reproducible.
NCI MATCH Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors or Lymphomas

NCI MPACT Molecular Profiling-Based Assignment of Cancer Therapy for Patients With Advanced Solid Tumors

John Hainsworth, et al (2016) MyPathway trial

Focus4 Trials a molecularly stratified, multi-site randomised trial programme for patients with colorectal cancer
Basket Trials
Basket and Umbrella Trials

I don’t know when exactly the terms ‘basket trial’ and ‘umbrella trial’ proposed, but the following articles used these terms and provided very good explanations about ‘basket trial’ and ‘umbrella trial’.

In, we can see many cancer trials are designed as basket or umbrella trials and the terms basket and umbrella trials may be explicitly indicated.

Basket and Umbrella trial design will require having a master protocol. Master protocol refers to one overarching protocol that includes one or more of the following:

  • Multiple diseases
  • Multiple therapies
  • Multiple biomarkers

Launching a clinical trial typically takes long time to go through the administrative (for example contract negotiation) and regulatory approvals (health authority and IRB/EC approvals). The master protocol can create an experimental plan to test several candidate drugs or conduct the trials in multiple diseases under a one protocol so that we don’t need to have a fresh protocol approval each time and minimize the delay caused by the clinical trial launching. It’s like a Plug and Play. Here is a slide presentation and a youtube video by Friends of Cancer Research for Lung Cancer Master Protocol Trial and a video by Dr Fred Hirsch who talked about the development of a master protocol.

To see what the master protocol looks like, the FOCUS4 clinical trial programme provides an excellent opportunity. All protocols including the master protocol and each of the umbrella protocols. The master protocol describes the overall study design and all common procedures across all umbrella protocols. The umbrella protocol provides information about procedures for entering patients into FOCUS4-A  after a patient has been registered through the procedures described in the FOCUS4 Master Protocol.

There are statistical considerations when we come to the master protocol, the basket trial, and umbrella trial. The operation of these trials will be more challenging than the usual single disease single drug trial. Statisticians need to embrace these new trial designs and adapt to the new paradigm of the clinical trial designs in the era of precision medicine. To this aspect, it is helpful to read Dr LaVange discussion on “Statistical Considerations in Designing Master Protocols

Further reading: