Research Note: Adaptive trials

The number of clinical trials published each year shows no sign of reaching a plateau, despite the cost of conducting a clinical trial rising five-fold over the past decade. Randomised clinical trials (RCTs) can have a profound and immediate impact on health policy and clinical practice, but while activity and quality have increased, only around half of all trials are published. Even when RCT evidence exists, there may be a failure to adopt this as best practice if the results are considered non-applicable to the specific patient at hand, or where there is mismanagement of commercial and academic interests, or other biases in the design, management, or reporting. Clinicians are often faced with the need to make treatment decisions across a range of comorbidities, whereas evidence from RCTs is predominantly presented for a single medical indication and frequently assumes homogeneity in participant responses. A one-size-fits-all approach to clinical trials is not in harmony with the heterogeneity and complexity of modern diseases. While the pipeline of new treatments is ever-increasing, the capacity to formally evaluate new treatments in RCTs is diminishing, due to the large inherent costs, overburdened healthcare system and low participation rates. Almost half of publicly funded trials do not meet recruitment targets, increasing the costs and the risk of inconclusive results. Although innovative solutions, such as adaptive designs, exist to improve trial efficiency, trialists rarely invest in the time and resources to simulate a broad range of enrolment and outcome scenarios; this is predominantly due to a lack of statistical expertise in trial simulation and the dearth of simple statistical tools with which to perform this function. Thus, most publicly funded clinical trials have simple parallel group designs (around 90% in the UK) that do not have inbuilt flexibility to adapt to accruing trial evidence. A single conservative stopping boundary applied after 75% of target recruitment could correctly allow early trial termination for futility in up to 30% of trials, saving participants from exposure to futile treatments and decreasing trial costs. Sub-optimal and deleterious treatments continue to be used, and RCTs are increasingly the preserve of large well-resourced pharmaceutical companies. Healthcare-embedded approaches that simultaneously evaluate and implement the best treatment option(s) might provide timely outcomes for participants that are resource-efficient, cost-effective, minimally biased, and accessible to all.