Clinical Trials in Small Populations: Challenges and Opportunities

In the inaugural event of the Global Cancer Movement, initiated by OncoDaily, Amalya Sargsyan, Medical Oncologist at Yeolyan Oncology and Hematology Center, discusses the critical role of clinical trials for small populations, including those from small countries, rare diseases, and regions with limited research access. The virtual event, held from December 6-8, 2024, brought together experts to explore innovative solutions and strategies to ensure broader inclusion in clinical research.

Coming from Armenia, a small country in the Caucasus with a population of only three million, this topic is highly relevant. Many people might perceive the challenges of small populations but could also identify the opportunities within these challenges. It is essential to first define what constitutes a small population.

A small population can be considered in various ways. It could refer to a small nation with a population of less than one million or even ten million. It could also relate to rare diseases, where the target population is naturally small due to the low number of affected individuals. Additionally, geographical challenges can lead to populations being underrepresented in clinical trials due to logistical difficulties. Furthermore, resource constraints in certain countries or medical centers can limit their participation in clinical trials.

Despite colorectal cancer being a common type of cancer, the recruitment of patients for trials remains challenging. The global burden of colorectal cancer is expected to increase in the coming years, affecting all nations, including smaller ones. Thus, it is crucial to make novel research accessible to all, regardless of population size.

When conducting trials in specific subtypes of common cancers such as colorectal cancer, the challenge of rarity emerges. For instance, if we start with 100 colorectal cancer patients, focusing on a specific genetic mutation like KRAS G12C, the eligible participants may dwindle to just a handful. This highlights the importance of identifying ways to overcome these challenges.

The example of EGFR mutations in lung cancer further demonstrates the importance of conducting trials tailored to specific populations. Initially, immunotherapy was seen as a breakthrough in lung cancer treatment, but different populations responded differently due to genetic variations. This underscores the necessity for even small nations to conduct their own trials to understand the unique genetic profiles of their populations and optimize treatment outcomes.

Small nations face several challenges when attempting to conduct clinical trials. Recruitment can be slow due to limited patient numbers. Additionally, there is often a lack of infrastructure and expertise, as healthcare professionals may not be familiar with the processes involved in clinical trials. Regulatory frameworks may also need adjustments to accommodate these trials.

Despite these challenges, failing to take action means that small populations will continue to be excluded from research and its benefits. Currently, most clinical trials are conducted in high-income countries such as the United States, China, and Japan. However, population size is not the only determining factor; collaboration, logistics, and income levels also play a role.

Collaboration is key for smaller nations. European countries with smaller populations have managed to participate in numerous trials due to strong collaborations. Forming partnerships and participating in international trials can help small populations contribute to the global research effort.

Innovative trial designs can also help overcome challenges. Conventional randomized controlled trials may not always be feasible, but alternative approaches such as multinational and regional trials can be more effective. Longer follow-up periods can help meet recruitment targets, and broader inclusion criteria can allow more patients to participate. Novel trial designs such as adaptive protocols and single-arm studies with historical or synthetic controls can further address these challenges.

Reducing sample size while maintaining statistical power is crucial. Trials should focus on treatments with significant differences from current standards to require fewer participants. Statistical methods, such as the Bayesian model, can optimize data analysis with smaller sample sizes by incorporating prior knowledge.

Using surrogate endpoints instead of overall survival and leveraging composite endpoints can also reduce sample size requirements while ensuring clinically relevant outcomes. It is crucial to maintain the quality and integrity of trials with the help of statisticians to balance clinical and research significance.

Small populations can contribute to global research by participating in larger trials and establishing their own registries and biobanks. Collaborations through consortia and joint actions for rare diseases have proven successful in pooling data and expertise. Building local infrastructure for trials can help small nations reduce dependency on larger centers and improve access to cutting-edge treatments.

The establishment of reference networks, such as those initiated by organizations like EORTC, aims to make trials more inclusive and diverse. This helps ensure the generalizability of results across various populations. Governments can support these efforts by providing funding and easing regulatory requirements to facilitate participation in international trials.

The future of clinical trials lies in decentralization, allowing smaller centers to participate in larger trials and expanding access to diverse patient populations. Regulatory networks should advocate for inclusivity, and novel trial designs should be embraced to overcome logistical and population-related challenges.

In conclusion, even the smallest elements matter in the grand scheme of scientific progress. By embracing collaboration, innovative trial designs, and regulatory support, small populations can play a vital role in advancing global medical research.