A clinical trial is a prospective study comparing the effects and value of intervention(s) against a control in human beings.
Two benefits are expected from randomisation:
Clinical trials testing new treatments are divided into different stages, called phases. The earliest phase trials may look at whether a drug is safe or the side effects it causes. Later phase trials aim to test whether a new treatment is better than existing treatments.
There are 3 main phases of clinical trials – phases I to III. Phase 1 trials are the earliest phase trials and phase III are later phase trials.
Some trials are randomised. This means the people taking part are put into one of the treatment groups at random. Doing this means the results are more reliable.
| Phase | Number of people taking part | Cancer type | Main aims of trial | Is it randomised? |
|---|---|---|---|---|
| I | Small – often about 20 to 50 people | Often lots of cancer types | Finding out about side effects, & what happens to the treatment in the body | No |
| II | Medium - tens of people, sometimes over 100 | Usually one or two cancer types, sometimes more | Finding out more about side effects & looking at how well the treatment works | Sometimes |
| III | Large - hundreds or thousands of people | Usually one cancer type, sometimes more | Comparing the new treatment to the standard treatment | Usually |
| IV | Medium to large, variable | Usually one cancer type, sometimes more | Finding out more about long term benefits & side effects | No |
They are usually small trials, recruiting only a few patients. The trial may be open to people with any type of advanced cancer, usually those who have already had all other available treatments.
Phase I trials aim to find out: - how much of the drug is safe to give (tolerability) - what the side effects are - how the body gets rid the of drug (pharmacokinetics and pharmacodynamics) - if the treatment helps shrink the cancer
Patients are recruited very slowly onto phase I trials. So even though they don't recruit many people, they can take a long time to complete.
They are often dose escalation studies. This means that the first few patients that take part (called a cohort or group) are given a very small dose of the drug. If all goes well, the next group have a slightly higher dose. The dose is gradually increased with each group. The researchers monitor the side effects people have and how they feel, until they find the best dose.
In a phase I trial you may have lots of blood tests because the researchers look at how your body copes with and gets rid of the drug. They carefully record any side effects you may have and when you have them.
The main aim of phase I trials is to find out about doses and side effects. They need to do this first, before testing the potential new treatment to see if it works. Some people taking part may benefit from the new treatment, but many won't.
A detailed description of the design and conduct of dose escalating trials for treatments of cancer is found in Chaps. 1–5 of a book edited by Crowley and Ankerst [Crowley J, Hoering A (eds.) Handbook of Statistics in Clinical Oncology (third edition). Boca Raton, FL: Chapman and Hall/CRC, 2012.].
Phase II. Not all treatments tested in a phase I trial make it to a phase II trial.
Phase II trials aim to find out: - if the new treatment works well enough to be tested in a larger phase III trial
- which types of cancer the treatment works for - more about side effects and how to manage them - more about the best dose to use
These treatments have been tested in phase I trials, but you may still have side effects that the doctors don't know about. Treatments can affect people in different ways.
Phase II trials are usually larger than phase I. There may be up to 100 or so people taking part. Sometimes in a phase II trial, a new treatment is compared with another treatment already in use, or with a dummy drug (placebo).
Some phase II trials are randomised. This means the researchers put the people taking part into treatment groups at random.
These trials are generally designed to assess the effectiveness of new interventions or existing interventions with new indications and thereby, their value in clinical practice.
Phase III trials aim to find out:
- which treatment works better for a particular type of cancer
- more about the side effects
- how the treatment affects people’s quality of life
They may compare standard treatment with:
- a completely new treatment
- different doses of the same treatment
- having the same treatment more, or less, often
- a new way of giving a standard treatment (radiotherapy for example)
Phase III trials usually involve many more patients than phase I or II. This is because differences in success rates may be small. So, the trial needs many patients to be able to show the difference.
Sometimes phase III trials involve thousands of people in many different hospitals and even different countries. Most phase III trials are randomised.
A procedure or device may fail after a few years and have adverse sequelae for the patient. In 2014, the FDA warned that morcellation to treat uterine fibroids by laparoscopic means, a procedure that had been used for years, could lead to spreading of unsuspected uterine sarcoma.
Bayesian design methods can be applied in Phase I and II. They involve the specification of the investigators’ prior opinions or require prior estimates.