A paper "Best practices case studies for 'less well-understood' Adaptive designs", has been published by the DIA Scientific Working Group on Adaptive Designs as a twin document to the previously discussed "Challenges and Opportunities of 'Less Well Understood' Adaptive Designs". This publication furthers understanding by reviewing 10 important case studies and sharing details on their design and operational characteristics, as well as related regulatory interactions.
To read an abstract and details of the full publication click here.
In this blog we'll take a look at some of the case studies under discussion.
The RAPTOR trial compared two formulations of cysteamine bitartrate: a delayed-release formulation (Procysbi) to an immediate-release formulation (Cystagon) in patients with nephropathic cystinosis. This case study is an example of an unblinded sample size re-estimation design. As we’ve previously discussed on the Cytel blog, the design was successfully implemented and led to regulatory approval for Procysbi.
The VALOR trial was an adaptive, 2-stage, phase III study evaluating safety and efficacy of vosaroxin as an add-on therapy to cytarabine in the treatment of patients with first relapsed or refractory acute myeloid leukemia. Robust upfront planning was required to fully consider the study design operating characteristics, and strong documentation developed to minimize operational bias.
The MERCK-VACCINE trial was a large adaptive, phase IIB/III outcome trial comparing the original Gardasil human papillomavirus (HPV) vaccine to the Gardasil 9 HPV vaccine in the prevention of cervical cancer. One of the potential drawbacks of this type of design is that the time between Phase 2 and 3 can be critical to fully absorb results, and interact with the regulatory agencies where required. However, because of the similarity of Gardasil 9 to a 4vHPV vaccine, for which extensive knowledge had been gained through another development program, this gap was not deemed necessary. Ultimately the trial was able to deliver operational efficiencies with time and resource savings and the product was approved in 2014.
The STAMPEDE trial is an ongoing open-label, randomized, controlled trial in prostate cancer using multiarm, multistage (MAMS) design. This study aims to simultaneously assess many treatments against a single control arm in a cost efficient approach. The approach also allows new suitable treatments to be incorporated after the trial has started. As with other kinds of adaptive design, significant upfront planning is required to facilitate the adding and discontinuation of arms.
To learn more about Multi- arm multi-stage trials as applied in Cytel’s East 6.4 click below to watch a presentation on the topic by Cyrus Mehta.
How do we define success in adaptive clinical trials?
As part of the conclusion of the article the authors ask an important question about how we actually define success in an adaptive clinical trial. They note that ' An AD is still valuable when it leads to an efficient study that directly or indirectly supports marketing approval, or when it demonstrates that a therapy is not viable' .They then go on to suggest that a better question might be ‘ Did the study meet its stated objectives? This latter is in the context of the objective of advancing the development program to the intended next stage as well as the immediate quantitative question at stake.
1) Miller, E., Gallo, P., He, W., Kammerman, L.A., Koury, K., Maca, J., Jiang, Q., Walton, M.K., Wang, C., Woo, K., Fuller, C. and Jemiai, Y. (2016) ‘DIAs Adaptive design scientific working group (ADSWG): Best practices case studies for “less well-understood” Adaptive designs’, Therapeutic Innovation & Regulatory Science, . doi: 10.1177/2168479016665434.
2) He, W., Gallo Paul, Miller, E., Jemiai, Y., Maca, J., Koury, K., Fan, X.F., Jiang, Q., Wang, C. and Lin, M. (2016) ‘Addressing challenges and opportunities of “Less Well-Understood” Adaptive designs’,Therapeutic Innovation & Regulatory Science, . doi: 10.1177/2168479016663265.