Innovative and Adaptive Designs in Clinical Studies
The Food and Drug Administration (FDA) had noted a decreased number of submissions for new drugs in 2004. This had raised FDA concern as pharmaceutical companies were slowly abandoning research for potentially life-saving drugs. The decreased interest of companies towards research had been associated with the growing costs and complexity of clinical trials. Pharmaceutical companies were hesitant to make such huge investments as the success rate of clinical drug development was low. To resolve this issue, the FDA launched the Critical Path Initiative (CPI) in 2004 to encourage innovation in the drug development process. An innovative design utilizing a more adaptive approach in clinical trials had been discussed by FDA under CPI in 2006.
Since then, different innovative and adaptive designs in Clinical studies have been proposed and implemented. These designs provide more flexibility as they allow adaption in a trial according to the accumulated results. Some of these designs are:
- Continual reassessment method: This design is used to identify maximum tolerated dose by combining all collected trial data with the data from the past trials.
- Group-sequential design: In this design, there is no predefined number of subjects to be enrolled. The subjects are enrolled and treated until significant results are achieved.
- Sample size re-estimation design: This design allows the reassessing the sample size of an ongoing clinical trial to get the required statistical power.
- Multi-arm multi-stage design: In this design, the decision of continuing or dropping a treatment arm is made based on the data collected by the interim analyses in the trial. Further subject enrollment is done for the arm that is selected to continue.
- Population enrichment design: In this design, subjects that are more likely to provide the required results are chosen to take part in the trial.
- Biomarker-adaptive design: In this design, biomarkers are used as an identifier for the selection of subjects for treatment.
- Adaptive randomization design: In this design, the allocation of subjects to a group is changed according to the collected data.
- Adaptive dose-ranging: In this design, subjects can be shifted to the better performing dose groups.
- Combination trials: In this design, two phases of a clinical trial can be combined to a single phase, e.g., a Phase II/III trial combining both Phase II exploratory and Phase III confirmatory stages.
- Multiple expansion cohorts: In this recently introduced trial design by FDA, multiple arms can be added to assess different objectives.
The implementation of these designs has significantly increased the number of new drug submissions and approvals. Adaptive designs in clinical studies allow for more effective, ethical and flexible conduct of the clinical trial. These designs also help to achieve faster drug approvals, thereby, providing potential life-saving drugs to patients with fatal diseases. The flexibility and economic nature of these designs also encourage pharmaceutical companies to invest more in research and development.
Although adaptive designs have been available for several years, the design is still not utilized as much as the traditional design. This may be linked to the lack of expertise required to utilize these designs, the fear of rejections from regulators for these designs or the lack of practicality of these designs in some cases. Pharmaceutical companies also may not know the instances in which these designs can be utilized, or they may not be aware of the benefits of using these designs in some situations. However, if these issues are resolved, innovative and adaptive approaches to clinical trials may revolutionize the drug development process.