Abstract
Despite high-level endorsement, the number of adaptive Phase II/III trials in rare cancers needs to be improved, with better understanding of their value for clinical decisions in daily practice. This paper describes approaches to trial design in rare cancers, which has been supplemented by a search of ClinicalTrials.gov for adaptive trial designs in rare cancer. In addition, an online survey of 3,200 oncologists was conducted. Practicing physicians were questioned on the importance of different evidence levels, types of adaptive trial design, and categories of surrogate endpoints for clinical decision making. The results of the online survey revealed that evidence from Phase II/III trials with an adaptive design and relatively small sample size was considered high value in rare cancer by 97% of responders, similar to the randomized controlled trial rating (82%). Surrogate clinical endpoints were considered valuable alternatives to overall survival by 80% of oncologists. Preferred adaptive designs were futility analysis, interim analysis, adaptive sample size, and adaptive randomization. In conclusion, rare cancer oncologists rate evidence from adaptive clinical trials with as high a value and importance for clinical decision making processes as conventional randomized controlled trials. All stakeholders have a vested interest in advances in clinical trial designs to ensure efficient and timely development of innovative medicinal products to allow more patients faster access to the pivotal treatment.
Highlights
Rare cancers have been variously defined as those with a prevalence of fewer than five cases out of a population of 10,000 (European definition) and cancers with fewer than 15 cases per 100,000 people per year (US National Cancer Institute definition) [1]
This paper aims to examine the potential value of adaptive clinical trials and surrogate clinical endpoints for clinical decisions in rare cancer
Regulatory agencies worldwide have instituted procedures for fast-track approval of innovative medicinal products (InMPs) for rare disorders and serious diseases, but it is recognized that innovative clinical trial designs are required to explore the potential of new agents in rare cancers
Summary
Rare cancers have been variously defined as those with a prevalence of fewer than five cases out of a population of 10,000 (European definition) and cancers with fewer than 15 cases per 100,000 people per year (US National Cancer Institute definition) [1]. Rare cancers accounted for 24% of all cancers diagnosed in Europe during 2000-2007 affecting around 4.3 million people [4], albeit with disparities in both incidence and survival between different countries [5], and 20% of cancers diagnosed in the USA during 2009-2013 [6]. The development of innovative medicinal products (InMPs) for rare cancers faces many challenges including difficulties in recruiting adequate numbers of patients from a very small and heterogeneous patient population, limited knowledge of disease natural history, and from a pharmaceutical company point of view: high financial investments, extensive development times, and significant risk of potential failure [7]
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