In November 2023, at Outsourcing Clinical Trials Dach in Zurich, our Executive Director, Oncology Strategy Lead, Matt Cooper, presented “Delivering Oncology Studies – Challenges and Considerations.” His presentation covered various aspects of oncology clinical programs, focusing on study design trends, with reference to both the recently implemented FDA Project Optimus guidance and studies we have seen from sponsors. Among these trends included:
Randomization
One key trend in oncology study design is a desire from the FDA to, where possible, move away from single-arm trials towards more randomized trials in the earlier setting. A randomized design can help alleviate some of the potential sources of bias in a trial, particularly regarding patient selection at higher doses. For initial dose-finding trials, they do not need to be powered to determine statistical superiority but instead should have sufficient patients to convey the trends between toxicity and dose efficacy.
There is also a move to take two dose levels out of Phase 1 and into Phase 2 to help define the best tolerated/effective dose more accurately. If two or more doses are discovered to have comparable efficacy, the lowest effective dose should be used in the registration trial to help minimize the toxicity effects when the drug is used in a broader heterogeneous patient population.
Biomarker Endpoints
Biomarker endpoints are another helpful way to assess the potential efficacy of both initial dose-finding studies and dose-optimization studies. To interpret early clinical data, it’s important to:
- Compare data from other compounds in the same drug class
- Utilize integrated pharmacokinetic (PK) and pharmacodynamic (PD) analyses
- Analyze the relationship between dose and exposure to efficacy and safety
In fact, success rates of trials using biomarker endpoints have been shown to be ten times higher than clinical programs that do not use them. You can learn more about biomarkers and how to use them in oncology studies in this white paper.
Statistical Design
Using statistical designs such as the Bayesian logistic regression model (BLRM) and Bayesian optimal interval (BOIN) trial designs are not only effective for identifying the maximum tolerated dose (MTD) but can also identify an optimal biological dose. Incorporating PK exposure and PD metrics, these statistical design models may establish a therapeutic window based on activity and an acceptable level of toxicity.
Master Protocols
An additional study design trend in oncology programs is the increase in master protocols, such as basket, umbrella, and platform trial designs:
- Basket Trial: Evaluates a single drug or combination in different tumor types.
- Umbrella Trial: Examines numerous drugs administered as individual drugs or combinations in a single tumor type.
- Platform Trial: Incorporates multiple drugs and/or different tumor types in various study arms. Additional arms can be added or removed during the trial at different times depending upon the signals seen, an almost semi-continuous trial.
One often cited platform study design is the Multi-Arm Multi-Stage STAMPEDE trial designed by the MRC Trials Unit in London. In this program, many drugs of interest were tested simultaneously against a standard control arm in a randomized controlled trial, with recruitment discontinued in arms that did not show sufficient activity. One of the trial arms provided data to the European Medicine Agency in the approval of abiraterone plus docetaxel for men with metastatic castration-sensitive prostate cancer.
Single-Arm Trial Design
Single-arm trials have also become an increasingly common development strategy to support regulatory approval and allow patients expedited access to novel therapies, particularly in the accelerated access setting. However, these types of trials can lead to small, non-comparative safety data sets and do not have the ability to use time-to-event endpoints. In some cases, the FDA has had to remove approvals of oncology drugs based on single-arm trials after they came to market because confirmatory studies had found that the safety/tolerability profile was less acceptable in the wider population.
Optimize Your Oncology Program with Worldwide
Matt Cooper and our global team of oncology experts have dedicated their careers to oncology clinical development programs. Leveraging our experience on more than 100 studies in the past few years and our awareness of recent study design trends, we can help ensure your oncology program stays on track to market approval.
