Phases in Clinical Trials: "Set Phases to Run!"

Even if you aren't working in clinical research, you will have likely heard of trial 'phases'. This term is often communicated in the media through social media posts, news articles and newsletters. But what are the different phases? How are they determined and when do they apply?

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Clinical trials took centre-stage in the 20th century and allow us to use the scientific method - in an ethical and considerate manner - to conduct experiments in human participants. While the first stage (appropriately named Phase I) was the first identified phase, phase's 0 and up to IV have come into play with their own strengths and footing. Here, we'll cover a brief evolution of trial phases.

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Phase 0: Exploratory, "Proof-of-Concept" Trials

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• Historical Context: Phase 0 trials emerged in the late 20th century. In drug research, the purpose of these trials was to help prevent exposure of human participants to interventions that did not have sufficient pre-clinical data‍
• Development: The concept of "Phase 0" gained momentum in the 1990s/2000s with the aim of obtaining early human data on pharmacokinetics and pharmacodynamics with minimal risk to participants‍
• Purpose and Benefits: Phase 0 trials can provide some early safety insights into drugs before launching into studies with larger numbers of people, thereby mitigating risks to health

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Phase I:

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• Historical Context: The concept of clinical trials was phase-less initially. Throughout the 20th century, the evolution of human participant trials underwent seismic shifts focussing more and more on ethics and safety. Phase I trials have consequently grown into studies which have a core focus on safety - before determining whether drugs or interventions actually have real-world therapeutic potential
• Development: Throughout the 1960's and 1970's, regulatory bodies such as the Food and Drug Administration (FDA) began to formalise the guidelines for clinical research involving human participants and emphasized the need for safety in humans, thus bringing about Phase I trials
• Purpose: Phase I trials have historically focused on determining the maximum tolerated dose in humans. They are typically carried out in a small number of participants

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Phase II: Exploratory Efficacy Trials

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• Historical Context: Moving a little on from safety, Phase II trials start to focus on product efficacy in larger cohorts.
• Development: As drug development became more complex in the late 20th century, systematic approaches to assess efficacy came into play.
• Purpose: Phase II trials aim to explore the therapeutic effect of a drug in a specific patient or participant population, providing a basis for decisions about further development. While efficacy is important, safety is still constantly monitored.

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Phase III: Confirmatory Trials

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• Historical Context: Early clinical trials with fewer participants lacked the ability to translate findings to populations at-scale. Smaller studies in earlier phase trials might have the potential to produce untrue findings or findings that are not relevant or impactful enough to broader populations. Regulatory bodies recognized this and the need for more rigorous studies
• Development: Larger scale randomised controlled trials (RCTs) took centre-stage here in the 1980's and 1990's and allow for more robust conclusions in a powered manner with sufficient participant numbers
• Purpose: Phase III trials are designed to confirm both the efficacy and safety observed in earlier phases and diverse populations or study subjects are key to achieving this objective

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Phase IV: Post-Marketing Surveillance Trials

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• Historical Context: Post-marketing surveillance has roots in pharmacovigilance efforts that have evolved over many years
• Development: As regulatory agencies became more proactive in monitoring drug safety, Phase IV studies gained significant prominence.
• Purpose: Phase IV trials are essential for assessing long-term safety and efficacy of drugs. Drugs at market which might be prescription or over-the-counter fall into this category as they become a staple of healthcare systems worldwide.

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Evolution of clinical trial phases is complicated, but one crucial consideration sits on the bedrock of this industry - participant safety and wellbeing. International communication and collaborating has been the cornerstone in helping bring together the trials and tribulations of drug research, as well as crucial refinements which continue to shape the industry at large.