I-Spy 2 Trial - a study with fancy name and fancy design

If you see the term “I-spy”, you would typically think something related to movie, kids game or TV series. Recently, I-spy has been linked to a novice clinical trial design in breast cancer.

For a short description about this study, clinicaltrials.gov is a good place. In clinicaltrials.gov, I-SPY 2 TRIAL is listed as “Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer”. For more detail descriptions about this study, you should check out the following websites:

• Barker et all (2009) I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy, Nature Translational Medicine
• Ispy2.org – I-Spy 2 clinical trial website
• I-Spy 2 Advocate Website – contains many presentations 
• An IT bundle to support adaptive trials with novel agents and emerging biomarkers

This study got a lot of publicities. For example, in FDA’s ‘advancing Regulatory Science for Public Health’, it specifically mentioned the I-Spy 2 trial,

“Personalized treatment for cancer

The “I-SPY 2 TRIAL,” launched in March 2010, represents a groundbreaking new clinical trial model that will help scientists quickly and efficiently test the most promising drugs in development for women with higher risk, rapidly growing breast cancers. During the trial, drugs in development are individually targeted to the biology of each woman’s tumor using specific genetic or biologi­cal markers, known as “biomarkers.” By applying an innovative trial design, researchers will use data from one set of patients’ treatments to treat other patients – more quickly eliminating inef­fective treatments and drugs. The I-SPY 2 trial was developed under the Biomarkers Consortium, a unique public-private partnership that includes the FDA, the National Institutes of Health, and major pharmaceutical companies, led by the Foundation for the National Institutes of Health. “

The claimed advantages for this trial design are:

• Utilized Personalized Medicine
• Uses genetic or biological marker (“biomarkers”) from individual patients’ tumors to screen promising new treatments, identifying which treatments are most effective in specific types of patients
• Improved Efficiency (fewer patients, less time, and fewer resources)

Enable researchers to use early data from one set of patients to guide decisions about which treatments might be more useful for patients later in the trial, and eliminate ineffective treatments more quickly Enable the development of more informed, smaller phase III trials

So what is this trial design? Can this trial really achieve its purpose? Here is what I would say:

• I-Spy 2 is a phase II study, anything generated from this study will need to be confirmed in Phase III confirmatory studies.
• I-Spy 2 is a government-sponsored study and supported by Foundation of NIH, Biomarkers Consortium, NCI, and others. It may never happen if it is an industry-sponsored study.
• I-Spy 2 is academic study and not a study for product licensure. If it is study for product licensure, there may be difficulties for study design to be accepted by regulatory agencies.

• I-Spy 2 design is complicated and it employs Bayesian Adaptive, Response Adaptive Randomization (play-the-winner approach), Biomarker Adaptive, Stopping and adding treatment arms. The algorithm and stopping rules are complicated and the assumptions / basis for generating these algorithms / stopping rules may eventually be demonstrated incorrect. 
• I-Spy 2 is a randomized, open label study. It would be more difficult to implement if this is a double-blinded study
• I-Spy 2 got it fame due to its use of ‘personalized medicine’, ‘adaptive design’ – all fit into the hot areas
• I-Spy 2 is a multi-center, NOT multi-national study. It would be much more challenging if this is a multi-national study

Although I-Spy 2 got a lot of attentions, not everyone is convinced with this design. The study is closed watched – let’s see the fate once it is completed.