Planning a Clinical Trial – Think Smart Design
By using smart designs, sponsors can save time and money while optimizing the knowledge accrued during the development of their products.
“Traditional” study designs and statistical methodology do not allow changing the main features of a study protocol once the study has been initiated. The use of interim analyses, and in particularly the development of group sequential analysis methods introduces some flexibility in the study designs by allowing interruption of treatment arms (or the whole study) after early demonstration of efficacy (or evidence of futility) at a planned interim analysis.
Advances in the methodology of clinical studies provide even more flexibility by allowing the modification of some features of the design based on information collected during interim analyses. Such a setup is known as an adaptive study design, or among other designations a flexible, smart or multistage design.
In its 2004 Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Product report, the US Food and Drug Administration (FDA) identified an urgent need to improve the efficiency and effectiveness of the clinical trial process, including trial design, endpoints, and analyses, and stated that in many cases, developers have no choice but to use the tools and concepts of the last century to assess this century’s candidates. In the following Critical Path Initiative Opportunities List (March 2006), adaptive designs are identified as one way to streamline Clinical Trials. The Regulatory bodies have issued guidance documents on the topic of adaptive designs. The EMA document was adopted in 2007 while the FDA draft guidance was issued in 2010.
The methodology experts at Venn Life Sciences have risen to the challenge by providing expertise and experience in helping clients to design such adaptive clinical studies.
So what is an adaptive design and how does it work?
An adaptive study design uses accumulating data to decide how to modify aspects of the study as it continues, without undermining the validity and integrity of the trial (Gallo et al. 2006). The design can be changed only if the modifications were prospectively planned and if sound procedures and statistical methods are employed that guarantee the control of operational bias and the correctness of statistical inferences.
Which study features can be adapted?
- Subject eligibility criteria (enrichment designs) can be modified
- Randomization ratio can be changed
- Treatment arms can be dropped, added to, or modified
- One could also consider modifying analytic methods or endpoints
- Studies combining objectives of two phases of development within one single design (e.g. a dose finding phase II objective combined with a phase III objective of confirmatory demonstration of efficacy within the same study constitute what is called a “seamless” adaptive design)
What are the pros and cons?
Beyond the practical advantages (faster, more efficient, and cheaper drug development) to such a “smart” design, the setup also has an ethical upside. Fewer patients are exposed to ineffective or harmful treatments and fewer patients are needed for the clinical development programs. From a business perspective, the more efficient clinical development process means that better decisions are made, resources are used more effectively and the final product is registered faster.
Designing an adaptive study sounds great, but it isn’t simple. The adaptations have to account for correct statistical inference, consistency between stages, minimized operational bias to avoid impacting the validity; further, integrity must be preserved by performing only pre-planned adaptations and by maintaining the blind to ensure that convincing results will be provided to the scientific community.
Moreover, an adaptive design requires rigorous planning and more complex statistical methods. It is undeniably an inherently complex procedure because of the need of interim analyses, independent data monitoring committee (DMC), independent statistical centre, and possible difficulties in regulatory buy-in.
What is the future of adaptive designs?
All these hurdles result in only a few adaptive designs being conducted. In a recent review, Hatfield et al  observed that the use of adaptive designs has increased from 11/10000 registered trials over the 2001-2005 period to 38/10000 over 2012-2013. The authors conclude that this rate remains low and that there may be disease areas in which ADs are being underutilised. We should expect more adaptive design trials to be conducted in the future, particularly in the early phases (exploratory trials) of clinical development.
Venn Life Sciences is up to the task of tackling the methodological and operational hurdles of adaptive designs for their clients. After the design phase is complete and the proposed study or development plan has been discussed with and approved by the regulatory authorities, Venn’s teams can implement it in the clinic to achieve everything from regulatory approvals and site selection to final statistical analysis and clinical study report writing. The company uses adequate logistical platforms, like interactive randomization technologies, electronic data capture, and a network of independent statisticians to prepare interim analyses for DMCs.
These powerful capabilities make it possible for Venn to implement and conduct successful adaptive clinical trials.
For further information please contact Venn France on +33 1 402 11 970 or check out www.vennlifesciences.com
1. http://www.fda.gov/ScienceResearch/SpecialT opics/CriticalPathInitiative/CriticalPathOppo rtunitiesReports/ucm077262.htm
2. http://www.fda.gov/downloads/ScienceResearch/SpecialT opics/CriticalPathInitiative/Critic alPathOpportunitiesReports/UCM077258.pdf
3.CHMP – Reflection Paper On Methodological Issues In Confirmatory Clinical Trials Planned With An Adaptive Design – October 2007– CHMP/EWP/2459/02
4.FDA – Guidance for Industry – Adaptive Design Clinical Trials for Drugs and Biologics – Draft Guidance – February 2010
5.Gallo P. et al – Adaptive designs in Clinical Drug Development – An Executive Summary of the PhMRA group – Journal of Biopharmaceutical Statistics, 2006, 16 : 275-283
6.Hatfield I, Allison A., Flight L, Julious S.A. and Dimairo M. – Adaptive designs undertaken in clinical research: a review of registered clinical trials – Trials 2016: 17 150: 1273-1279
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