Early Phase Trial to Find Maximal Tolerated Dose (MTD) - 3+3, CRM, and BOIN Designs

In early-phase clinical trials, determining the dose range and therapeutic window is critical. The purpose of the early-phase studies may just be to identify the maximum tolerated dose or maximum tolerable dose. 

Definition of maximum tolerated dose (MTD)

The highest dose of a drug or treatment that does not cause unacceptable side effects. The maximum tolerated dose is determined in clinical trials by testing increasing doses on different groups of people until the highest dose with acceptable side effects is found. Also called MTD.

The studies for identifying the MTD are usually designed as a dose-escalation study and the dose-escalation study is defined as:

A study that determines the best dose of a new drug or treatment. In a dose-escalation study, the dose of the test drug is increased a little at a time in different groups of people (also called cohort) until the highest dose that does not cause harmful side effects is found. A dose-escalation study may also measure ways that the drug is used by the body and is often done as part of a phase I clinical trial. These trials usually include a small number of patients and may include healthy volunteers.

In dose-escalation studies, within each dose cohort, a placebo group can be included even though the majority of the dose-escalation studies for MTD are designed without placebo controls.

Identifying MTD is based on the number of dose-limiting toxicities (DTLs)that are observed in each dose cohort. DTLs are defined as: 

side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment.

In practice, DTLs are often defined as grade 3 or above adverse events according to Common Terminology Criteria for Adverse Events (CTCAEs) especially in the oncology area even though other customer-defined criteria for DTLs may be used in non-oncology areas. 

Clinical trials to identify the MTD are generally needed for phase I studies directly conducted in patients, not healthy volunteers. Areas that the phase I studies are conducted in patients, not healthy volunteers, include oncology drugs, drugs in severe diseases such as AIDS, Sepsis, ARDS, etc., the gene and cell therapies, human-plasma derived products.

There are different types of clinical trial designs for identifying the MTD. The commonly used designs are 3+3 design, Continuous Reassessment Method (CRM), and Bayesian Optimal INterval design (BOIN). 

3+3 Design was discussed in an early post Phase I Dose Escalation Study Design: "3 + 3 Design". It is a straightforward rule-based method and requires no statistical calculations. 3+3 design is the most frequently used method for identifying the MTD. 

The CRM is a model-based design for phase I trials, which aims to find the maximum tolerated dose (MTD) of a new therapy. The CRM has been shown to be more accurate in targeting the MTD than traditional rule-based approaches such as the 3 + 3 design. With CRM design, statistical inferences on the model parameter(s) need to be made using likelihood-based or Bayesian approaches and DLT probability at each dose needs to be estimated. The patient is assigned to the next dose level based on the probability of patients with DLTs at the current dose level. The toxicity risk of other dose levels is based on accrued data, which improves trial efficiency. 

Following articles or videos provided a great introduction/reference about the CRM method: 

• Wheeler et al (2019) How to design a dose-finding study using the continual reassessment method
• Garrett-Mayer:  The continuous reassessment method for dose-finding studies: A tutorial
• PHASE I CLINICAL TRIALS:CONTINUAL REASSESSMENT METHOD (CRM)
• O'Quigley, Pepe, Fisher (1990) Continual reassessment method: a practical design for phase 1 clinical trials in cancer

The BOIN design shares the simplicity of the 3+3 design, which makes the decision of dose escalation/de-escalation by comparing the observed DLT rate with 0/3, 1/3, 2/3, 0/6, 1/6, and 2/6. The BOIN design makes the decision by comparing with two fixed boundaries, λe and λd, which is arguably even simpler.

BOIN design are described and explained in the following article and video:

• Yuan, Hess, et al (2016) Bayesian Optimal Interval Design: A Simpleand Well-Performing Design for Phase IOncology Trials
• BOIN: a novel platform for designing early phase single-agent and drug-combination clinical trials

Software for Sample Size Calculation for Phase I MTD Finding Studies:

• Cytel's EAST software has a module 'ESCALATE' containing the sample size calculations for 3+3, CRM, BLRM, mTPI, comb2BLRM, and PIPE methods. 

• trialdesign.org is a website developed and maintained by a research team at MD Anderson Cancer and it contains the literature and software for phase I designs including CRM and BOIN. 

Additional Videos: 

• Detangle modern dose-finding designs: A tutorial
• Designs of dose escalation studies in phase I oncology trials
• Practical Model-based Approaches for Phase 1 Oncology Trials
• Phase 1 Dose Escalation Trials with ESCALATE