Principles of New Trial Designs and their Practical Implications
|EUPATI Open Classroom
|Clinical Trials and Trial Management
|Principles of New Trial Designs and their Practical Implications
|Monday, 4 March 2024, 11:41 AM
Table of contents
- 1. Introduction
- 2. Adaptive Designs
- 3. Possible Approaches in Adaptive Design
- 4. Patient Involvement
- 5. Further Reading
(This section is organised in the form of a book, please follow the blue arrows to navigate through the book or by following the navigation panel on the right side of the page.)
2. Adaptive Designs
2.1. Adaptive Designs in Rare Diseases
- They shorten the development process without compromising validity or efficacy.
- Ineffective treatments can be identified earlier on.
- They permit a more efficient use of resources.
3. Possible Approaches in Adaptive Design
- Major design elements may be changed (for instance dropping treatment arms).
- Statistical uncertainty (for instance bias, variability, incorrect selection).
- Estimation of the treatment effects (beneficial or adverse).
- Control of statistical errors and operational biases are of utmost importance.
- Strong control of Type I errors is required (for example, finding a treatment efficient when it, in fact, is not).
3.1. Example 1: Group Sequential Design
- At Interim 1, for futility based on progression-free survival (PFS) – whether the patient stays free of any progression of a specific cancer or not.
- At Interim 2, for futility or efficacy based on overall survival.
Group sequential design allows for early stops on the basis of progression-free survival or overall survival. In this example, participants were randomised onto one of two arms, and received either Treatment 1, or a combination of Treatment 1 and Treatment 2.
3.2. Example 2: Multi-arm, Multi-stage Design (MAMS)
Advantages of the MAMS design
- Fewer participants
In this design, several trials are performed at once, which helps reduce the number of participants randomised to the control arm.
- Less overall time required for medicine discovery
The intermediate steps of the MAMS design replace the separate Phase II step. The decision on whether the medicine is sufficiently active is incorporated as a pilot phase into this trial.
- Fewer applications and approvals required
Regulatory work is done for one trial instead of for multiple trials.
Uninteresting arms can be dropped and new arms can be added.
- Reduced cost
This trial design requires fewer participants, fewer regulatory applications, and less overall time, all of which help to save on development costs.
Disadvantages in MAMS design
- Operating characteristics
Because of the complexity of this approach, it may be difficult to manage and requires a lot of simulations during the design process.
- Required number of participants
This depends on the operating characteristics, but if treatment arms are added during the course of the trial, it may be difficult to predict budget and regulatory issues.
- Trial duration
If treatment arms are added, it becomes difficult to predict when the trial will naturally end.
- Continued accrual (recruitment) to control arm
In order to avoid a time bias when new treatment arms are added, recruitment to the control arm must continue throughout the course of the trial. Consideration must also be given to what happens if a new standard of care becomes available during the course of the trial – is the control still relevant?
- Comparison between experimental arms
The MAMS design only allows for comparisons between individual treatment arms and the control arm; it does not allow for comparison between individual treatment arms themselves.
3.3. Example 3: Seamless Phase II/Phase III Design
Phase II/III design
The seamless Phase II/III design allows Phase II and Phase III to be performed in the context of one trial.
Advantages in Seamless Phase II/Phase III design
- Helps to mitigate bias
Both steps are conducted independently and the results of both steps are combined in the end in an overall test result.
- Shortens time and participant exposure
Phase II and Phase III are performed within the context of one trial.
The way that the treatment arm for final comparison is chosen in the Phase II part and merged with the Phase III part is relatively flexible.
Efficient use of resources
Participants from Phase II and Phase III both contribute data to the final results.
- Complicated statistical analyses
This design requires statistical aspects that are not so straightforward.
- Recruitment gaps
There is a gap in the recruitment between the two phases while waiting for enough data to be gathered in order to perform the interim analysis that decides whether to continue or not.
- Logistic challenges
This design is logistically challenging – it requires a quick flow of data so that the number of events in the analysis can be followed up on.
- Difficulties arising from long-term endpoints
This design requires information on PFS to be available relatively quickly. This becomes more difficult when the endpoints are long-term.
- Risk of lost information
Combining two arms risks the loss of information.
3.4. Example 4: Responsive-Adaptive Randomisation
5. Further Reading
- Clinical Trials Planned with an Adaptive Design (2007): Available at: Reflection Paper on Methodological Issues in Confirmatory Clinical Trials Planned with an Adaptive Design (europa.eu)
- Chow SC, Chang M. Adaptive design methods in clinical trials - a review. Orphanet J Rare Dis. 3(11) May 2008: Available at: 1750-1172-3-11.pdf (biomedcentral.com)
- I. Judson, J. Verweij, H. Gelderblom, et al. Results of a randomised phase III trial (EORTC 62012) of single agent doxorubicin versus doxorubicin plus ifosfamide as first line chemotherapy for patients with advanced or metastatic soft tissue sarcoma: a survival study by the EORTC Soft Tissue and Bone Sarcoma Group.
- Sydes MR, Parmar MK, James ND, et al. Issues in applying multi-arm multi-stage methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial. Trials. 10 (39) Jun 2009: Available at: 1745-6215-10-39.fm (nih.gov)
- Kairalla JA, Coffey CS, Thomann MA, Muller KE. Adaptive trial designs: a review of barriers and opportunities. Trials. 13 (145) Aug 2012: Available at: 1745-6215-13-145.pdf (biomedcentral.com)
- Cytel Webinar for East®SurvAdapt. October 28, 2010: Available at: d:\cyrus-office\working\East-SurvAdapt-Webinar.dvi (cytel.com)