Unfavorable results during the clinical phase studies will put a damper on the drug’s journey to market. Traditionally, pharmaceutical manufacturers should have a clear hypothesis and realistic endpoints of the trial. An adaptive design clinical trials allows more flexibility in clinical studies by allowing modifications to the trial. The modifications can be done after the trial has started without undermining its validity and integrity. Pharmaceutical manufacturers must navigate a maze to select the best adaptive design clinical trials to get their drug to market expeditiously. Currently, there are many types of adaptive clinical trial designs, so for simplicity, this article will discuss the following clinical trial designs:
- Adaptive Dose-Finding Design
- Drop-the-Losers Design
- Adaptive Group Sequential Design
Adaptive Dose-Finding Design
As the name may suggest, this adaptive design clinical trials focuses on ascertaining the most effective dose. The design allows the sponsor to select multiple doses across a range, which is used to identify the minimum effective dose and the maximum tolerable dose. As the clinical trial progresses, the dose groups decrease as unsuitable doses are identified. This clinical trial design also allows the sponsor to add new doses based on interim analyses. A clear benefit of the adaptive dose-finding design is potential toxicity and ineffectiveness is reduced since participants enrolled later in the study would have avoided the dose groups that were terminated.
After review of interim data analyses, the sponsor may have the option to drop inferior treatment groups. This clinical trial design allows the sponsor to modify or add new treatment arms if needed. It is beneficial to use this design during initial phases when appropriate dose and frequency needs to be determined. Another useful way to use this clinical trial design is when comparing treatment options in a later phase. The design is commonly used as a two-stage design, where the inferior arms are dropped at the first stage and the winners then proceed to the next stage.
Adaptive Group Sequential Design
The adaptive group sequential design does not have a fixed sample size. Instead, collected data is reviewed and if pre-selected criterion is met, then the sponsor may terminate the trial or add other adaptations. The pharmaceutical company or the contract research organization (CRO) may make the following adaptations:
- Modification of treatment arms
- Sample size re-estimation
- Dose selection
- Duration of treatment
- Change of study endpoints
- Modification of treatment use
An additional benefit of this adaptive clinical trial design that the sponsor may find appealing is the ability to discontinue the study if its primary objective is not met. This benefit will allow the sponsor to save valuable resources and avoid unnecessary exposure to participants.
Pharmaceutical companies and their CROs should evaluate the pros and cons of each adaptive design clinical trial. Overall, adaptive design clinical trials allow an increased opportunity to find safe and effective treatments. Although an adaptive clinical trial design can have major pitfalls, such as type I errors, moving target populations, or lost safety data, it has many benefits when selected and developed carefully. The FDA and EMEA are leading the way for the acceptance of sponsors using adaptive design clinical trials. Adaptive design clinical trials provide increased flexibility, efficiency, and speediness, allowing faster market delivery of life-saving drugs.
Christina Sanchez Miller, MPH has over 20 years of management, biologics, quality assurance and research experience in the medical field. She is a published author in scientific books, papers and has presented at several international conferences. Christina has developed medical applications in the biologics field. Her experience includes operations and consulting in FDA Adverse Event Reporting, FDA Product Deviation Reporting, FDA 483’s, cGTP’s, infection control, certified ISO Class 5, 7, 8 development and maintenance, QIC and auditing.
Pharmaceutical Development Group (PDG) is a global scientific & regulatory consulting firm with extensive experience in the strategic development of drug products, biologics, medical devices, combination products and FDA regulatory affairs. PDG is a pharmaceutical consulting group focusing on NDA regulatory services, adaptive clinical trial design, and IND consulting services. PDG is a subsidiary of Biotech Research Group Corporation.