Changing regulations, challenging study designs, and globalization
Early-phase trial designs are becoming more complex following the US Food and Drug Administration’s Project Optimus guidance. The guidance highlights the requirement to explore the optimal biological dose for the investigative medicinal product under development, moving away from dose selection based solely on toxicity (maximum tolerated dose). This guidance has resulted in early-phase trials requiring increased patient numbers as dose selection is optimized and increased pharmacokinetic (PK) and pharmacodynamic (PD) data. Historically, Phase I trials were conducted within a single country with expansion into multiple regions for Phase II, however, it is now common for Phase I trials to be multi-country.
Larger, more global early-phase oncology trials
Under the backdrop of precision medicine comes the requirement for more selective patient populations driven by tumor-specific markers. Finding enough patients to participate in clinical trials can be slow and challenging, hence the requirement to broaden the geographical footprint even for early-phase trials. These changes have resulted in increased costs of running early-phase oncology trials on top of a restrictive funding environment, putting significant pressure on small biotechnology companies.
Integrated and more innovative trial designs
Gone are the days of simple Phase I monotherapy dose escalation trials. There is now a noticeable trend towards combining Phase I and Phase II oncology trials. Traditionally, Phase I trials focus on determining the safety and dosage of a new treatment, while Phase II trials evaluate its efficacy. There are numerous benefits from combining these phases, including streamlining the drug development process, reducing costs, and accelerating the timeline for bringing new treatments to patients. This approach also allows researchers to gather preliminary efficacy data earlier, which can inform decisions about whether to proceed with further development. It helps identify potential biomarkers and patient subgroups that may benefit most from the treatment as well. Phase I/II combined trials often include both monotherapy and combination-therapy, dose-escalation arms followed by multiple expansion cohorts in specific patient populations.
Retiring 3 + 3 dose escalation trial design
Phase I trial designs have evolved significantly from the traditional 3 + 3 dose escalation trials. Some key changes include:
- Bayesian adaptive designs: Use statistical models to adapt the trial based on accumulating data, allowing for more efficient dose-finding and better identification of the optimal dose.
- Model-based approaches: Use mathematical models to predict the relationship between dose and response, improving the accuracy of dose selection.
- Expansion cohorts: Added to Phase I trials to evaluate additional doses or patient subgroups, providing more data on efficacy and safety.
- PK and PD modelling: Help to understand a drug’s behavior in the body and its biological effects, guiding dose selection more precisely.
- Patient-centric designs: Make trials more personalized and often incorporate biomarkers and molecular profiling to select patients who will most likely benefit from the treatment.
Increasingly complex trial logistics
The development of innovative treatment modalities and trial designs has resulted in increased logistical challenges for running clinical trials.
Comprehensive data collection: Project Optimus promotes collecting extensive dose-response and exposure-response data to better understand the drug’s profile. This has resulted in an increase in sample collection and the corresponding sample processing and analysis. The trend toward combination trials has added the additional challenge of complex toxicity profiles requiring additional safety monitoring.
- Trial supplies: Managing multiple vendors, customs regulations, and transportation logistics can extend timelines and increase costs. Many trial materials, especially biologics, require specific temperature conditions during storage and transport. Maintaining these conditions and supplies globally can be complex and costly. Accurate forecasting and inventory management are essential but challenging due to unpredictable patient enrollment rates and study timelines.
- Resource allocation: The shift toward integrated Phase I/II trials and expansion cohorts means that more resources—time, personnel, and funding—are needed upfront. This can strain budgets and require careful planning to ensure efficiency.
- Patient recruitment and retention: Patient-centric designs and the use of biomarkers can improve patient recruitment and retention by targeting the right patient populations. However, they also require more detailed screening and follow-up, which can add logistical challenges.
Clinical trial multi-regional requirements
The change to integrated trial designs and more tailored patient populations has led to the inclusion of multi-regional trials earlier in the drug development pathway. More trials are being conducted across multiple countries and regions. This is also being driven in part by the FDAs guidance for inclusion of diversity action plans and draft guidance on conducting multi-regional clinical trials in oncology.
Companies are encouraged to build diversity plans into their drug development pathway to ensure that trial data is representative of the final patient population the treatment will benefit. Trials need to be designed to account for regional variability in patient populations, disease prevalence, and treatment practices.
The changing oncology development landscape offers much promise for the future of cancer research. While these changes aim to make oncology clinical trials more efficient, effective, and patient focused, they also introduce new complex trial designs and logistical challenges that require careful management and planning.
We can help
With our exclusive biotech focus and oncology experience, Catalyst Oncology supports early- to late-phase drug development across both solid and hematologic indications. Reach out to learn how we can support the successful conduct of your next oncology trial.
