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KEY CONCEPTS

  • Dose selection by a phase I/II trial should be based on efficacy rather than the maximum tolerated dose (MTD), among dose levels with acceptable toxicities.

  • A response-adaptive randomization (RAR) schema must control covariate imbalance between the treatment arms to guarantee valid comparison results between them.

  • A personalized RAR is used to assign each individual to the treatment arm that fits them best based on their biomarkers.

  • An efficient RAR accounts for both tumor response and survival.

  • An innovative statistical design for target therapies is proposed to consider both the overall effects and effects for an unknown sensitive subset whose signature is to be identified from the ongoing trial.

  • A new enrichment design selectively enrolls sensitive patients during the trial while keeping updating the selection criteria for sensitive patients as the trial proceeds.

A BRIEF INTRODUCTION OF THE DRUG DEVELOPMENT PROCESS

Public Significance of Efficient Statistical Design for Clinical Trials

Based on the analysis of National Institutes of Health (NIH), the medical cost associated with cancer was $124.6 billion in the United States in 2010, and it was expected that the expense would reach $158 billion by 2020 as the prevalence of cancer increases.1 The skyrocketing cost of drug development is one of the top contributing factors for the high-cost healthcare system in the United States. One generally accepted estimate for preapproval cost of new drug development is about $0.8 billion.2 Studies have shown that for every 5000 to 10,000 compounds that enter the research and development pipeline, ultimately only one can reach the market.3 When considering all failed development programs, the cost per successful new drug will be even more expensive. Because all the costs in drug development will eventually be passed down to patients and healthcare system payers, a cost reduction in the drug development process can lower the financial burden on the US health care system.

To effectively reduce the cost and speed up the drug development process, collaborative efforts from all relevant parties are necessary. The role of biostatisticians in a clinical study team is to design a sound clinical trial that can generate high-quality data and analyze data appropriately so the intended scientific questions can be answered correctly with minimum bias and adequate quantification of uncertainty. Therefore, biostatisticians can help to reduce the cost of drug development by implementing innovative statistical methods that can help shorten the duration of a clinical trial and enable physicians to make better informed decisions through more efficient use of existing data.

The Process of Drug Development

The first step in the drug development process is “Discovery,” which often begins with the identification of a suitable target. The target normally is a molecule or a protein receptor or a gene that is specifically associated with a disease condition or pathology. For this purpose, researchers are required to have thorough ...

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