Clinical trial phases explained: from first-in-human to post-marketing

Developing a new medicine is a long, carefully regulated process. Before a drug can be sold in a pharmacy or prescribed by a doctor, researchers must prove that it is safe and that it does what it is supposed to do. This proof is gathered through clinical trials—studies that test new treatments in human volunteers. These trials happen in distinct stages, known as phases, each with a different purpose. Moving from one phase to the next is never guaranteed; in fact, most potential medicines fail long before they ever reach the public. Understanding these phases helps explain why new medicines take years to develop and why the process is so rigorously controlled.

Before human trials: Pre-clinical research

Before a medicine is ever given to a human, it undergoes pre-clinical research. This stage usually involves laboratory studies and testing on animals or cells. The goal is to gather basic information about how the medicine works, whether it is toxic, and what a safe starting dose might be. If this research looks promising, the developer applies to a regulatory authority for permission to begin testing in humans. In South Africa, the South African Health Products Regulatory Authority (SAHPRA) oversees and must approve any clinical trials conducted within the country before they can begin. Only a small fraction of compounds that look promising in the laboratory make it past this stage and into human trials.

Phase I and Phase II: Safety and early signs of efficacy

Phase I is the first time a medicine is given to humans. These trials are generally small, often involving somewhere between 20 and 100 healthy volunteers, though sometimes they include people with the condition the drug aims to treat. The primary goal is not to cure or treat, but to evaluate safety. Researchers look at how the body absorbs, distributes, and eliminates the medicine, and they monitor closely for side effects. This phase helps establish a safe dosage range.

If Phase I shows the medicine is safe enough to continue, it moves to Phase II. Here, the trial expands to a larger group—often a few hundred people who actually have the condition being targeted. Phase II tests whether the medicine has any beneficial effect and continues to monitor safety. This phase is a common point of failure; a medicine might be safe, but if it does not show enough of a positive effect on the disease, development will stop.

Phase III: Large-scale testing and regulatory approval

Phase III trials are the largest and most expensive part of the development process. They commonly involve hundreds to several thousands of participants across multiple locations, sometimes globally. The goal is to confirm the medicine’s effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the medicine to be used safely.

These trials are often randomised and controlled, meaning participants are randomly assigned to receive either the new medicine, an existing standard treatment, or an inactive substitute (a placebo). This helps ensure the results are scientifically sound. Because of the large numbers of people involved, rarer side effects that might not have appeared in earlier phases can be detected. Many medicines fail during clinical development, and Phase III is where several are abandoned due to lack of effectiveness or unexpected safety concerns. If Phase III is successful, the developer submits the data to regulators to request approval to market the drug.

Phase IV: Post-marketing surveillance

The testing does not stop once a medicine is approved and available for prescription. Phase IV trials happen after the medicine is on the market. The goal is continued pharmacovigilance—monitoring the medicine in the real world, where it is used by a much larger and more diverse population than in clinical trials.

Because earlier phases only test the medicine on thousands of people at most, very rare side effects may only emerge once millions of people are taking it. Phase IV studies also look at long-term effects, how the medicine interacts with other common medicines, and whether it works differently in specific populations. If significant safety issues are found during this phase, regulators may add warnings to the label, restrict its use, or in rare cases, withdraw the medicine from the market entirely.

Why most candidates fail

The high failure rate of clinical trials is a feature of the regulatory system, not a flaw. Many compounds show promise in laboratory settings but behave very differently in the complex environment of the human body. Some fail because they are not effective enough to justify approval, others because they cause unacceptable side effects, and some simply because they are not any better than treatments that already exist.

This rigorous filtering process is designed to ensure that the medicines which do eventually reach patients offer a genuine benefit that outweighs their risks. Patients and healthcare professionals can use resources like HealthSA to verify the registration status of medicines in South Africa, ensuring they are using products that have successfully passed through this rigorous evaluation process.