Treatment training manual

8. 4 Developing a new drug: phase 1, 2, 3 and 4 studies

When a new drug is being developed, there are four main phases of research.

These human studies are run in chronological order. They start with phase 1, before moving on to phase 2 etc.

Pre-clinical studies refer to earlier studies. These include the test-tube and animal studies before a drug can be tested in humans.

Phase 1 studies

Phase 1 studies are the first human studies.

This includes single-dose studies that are often called phase 1a trials. A small group of people (ie 5-10) will take one single dose and be carefully monitored. 1-2 participants will usually get a placebo (an inactive dummy pill). This is the control arm.

Phase 1b studies are short-term multi-dose studies, perhaps for 1-2 weeks. This is where a slightly larger group (perhaps 10-20 people) take several doses.

Phase 1 studies usually enrol people who do not have the condition that is being treated. So the first people to take an experimental HIV drug are usually HIV negative. They are often called ‘healthy volunteers’ although this is not really accurate.

It would be better if they specified HIV negative as HIV positive people are often healthy and HIV negative people might, for example, be unhealthy smokers. Participants are often paid in Phase 1 studies so they are not really volunteers either.

Phase 2 studies

Phase 2 studies give the first results about whether a compound is actually active. They are run in HIV positve people where viral load will be monitored very closely over a short period.

Phase 2 studies can last a day, a week or two, or several months. Phase 2a studies usually enrol 20-100 people.

Phase 2b studies also look at different doses of a drug. These are called ‘dose-finding’ studies. In this case they might enrol 200-300 people.

Phase 3 studies

Phase 3 studies produce the main evidence about whether a drug is safe and effective. These are usually large international studies that might enrol several thousands participants for a new HIV drug.

Phase 3 studies produce the main evidence that decides whether a drug will be approved. This decision is made by different regulatory agencies.

Two important agencies are the European Medicines Agency (EMA) in Europe and the Food and Drug Administrations (FDA) in the US.

Phase 3 studies for an HIV drug usually enrol 400 – >2,000 participants, depending on how the drug is likely to be used.

If the same participants in a phase 2 study continue into phase 3, the study is sometimes called phase 2/3.

If one study leads into another, this is called a ‘roll-over’ study.

Phase 4 studies

Phase 4 studies are also called post-marketing studies. This is because they are run after a drug has been approved and licensed.

Phase 4 studies involve longer follow-up and look at side effects and other safety concerns. Side effects that are either very rare or that take years to develop are often only seen after a drug is approved, and after it has been widely used by tens of thousands of people.

Phase 4 studies are usually recommended by regulatory agencies like the EMA or FDA. Sometimes they are a condition of the drug approval process. However, many companies never complete these phase 4 studies.

Agencies like the FDA and EMA used to have very little power to make sure companies completed phase 4 commitments. Recent legislation has tried to strengthen their authority.

In the EU, phase 4 studies are now compulsory and the EMA can withdraw a medication if safety commitments are not followed.

Last updated: 1 January 2023.