Clinical Trials: The 5Ws

How do doctors know that a new drug is safe and effective to give to patients?

The answer lies not only in research, but in clinical trials. These trials involve real patients testing new treatments, but how exactly do they work?

When?

The first clinical trial conducted by a physician took place in 1747 by Dr James Lind aboard a Naval ship called the Sailsbury. His trial, involving just 12 sailors aimed to find a cure for scurvy, a disease that plagued many long-distance sailors caused by low levels of vitamin C.

Fast forward to the 1950s, the first clinical trial focusing on a treatment for cancer took place. The trial tested a chemotherapy agent called mechlorethamine on a small group of patients with lymphoma, a type of blood cancer affecting white blood cells in the immune system.

Fast forward again to 2023 and, according to the World Health Organisation, 2,254 clinical trials enrolled their first trial participant in the UK. 20% of these – 378 trials – were focused on cancer. These modern trials differ in many ways from the early physician-led clinical trials- today’s are far more rigorous, result from years of preclinical research, follow well-structured phases and involve thousands of patients.

What?

A clinical trial is divided into four defined phases. The drug or treatment must meet the objectives of the study in order to progress from one phase to the next. For example, the drug must be shown to be beneficial compared to standard treatments to move from phase 3 and be approved at phase 4.

If this doesn’t happen, the drug or treatment is likely discontinued. Although, in some cases, the drug or treatment can be modified and repurposed if there is an indication that it may have promise for other conditions.

Why?

Clinical trials are essential to ensure that new treatments are safe and effective.

It may seem risky to test a drug in people, but it is absolutely necessary and only happens after years of what researchers call preclinical research.

Preclinical research typically involves two stages. The first is in vitro testing, where the drug or treatment is studied in cells or tissues outside of the body, in the laboratory.

The second stage is in vivo testing, where the drug or treatment is tested in a whole, living organism- in cancer research, this is usually an animal. This is to understand how the drug or treatment will work in the body and whether it has any unwanted side effects.

Preclinical research also involves pharmacological testing to understand how it interacts with the body and how the body processes the drug to make sure that it works and remains stable. This is required by regulatory bodies before a drug can be tested in a clinical trial, but is separate from the early preclinical research that is done at the Manchester Cancer Research Centre (MCRC).

Even after extensive preclinical testing, a clinical trial is essential to confirm that the drug or treatment is safe for humans. Research in cells and animals provide valuable insights, but factors like dosage and side effects must also be confirmed in people, as results from in vitro and in vivo work do not always directly translate to humans.

Animals in research

Scientific research involving animals is crucial for improving our understanding of health and disease as well as for developing new drugs and treatments for patients. It only takes place when there is no alternative.

All research involving animals is carried out under strict ethical guidelines and the animal’s welfare is balanced against the scientific need of the study at every step. The animal’s health is monitored daily, and any problems are immediately addressed. The animals are usually housed in groups, in cages that have environmental enrichment for their comfort.

At the Cancer Research UK Manchester Institute facility, the only animals used in research are mice. Mice are a good model for research as their genes are very similar to humans.

The facility supports researchers based within the MCRC partnership with 17 different cancer research areas each comprising several projects that involve the use of animals. On average, these projects use between 200 to 600 mice per year.

All research projects involving an animal are carefully considered by the Institute’s Animal Welfare and Ethical Review Body before being sent to the Home Office for approval. The 3Rs of replacement, reduction and refinement guide the use of animals in scientific research. This means that ways to reduce the number of animals involved, the refinement of methods to improve animal welfare, or the use of replacement methods without animals all have to be considered before a project can be approved.

Who?

Each clinical trial has a list of criteria a patient has to meet in order to take part. Mostly, the criteria relates to the type and stage of a person’s cancer, and any previous treatments they may have had. This is because trials tend to focus on only one type, or related types of cancer, and because different drugs may interact with one another, producing harmful side effects or reducing their effectiveness.

A person’s general health and medical history is also important, particularly if they have a health condition that may be made worse by a potential side effect of the drug or treatment being tested.

It’s a careful balance, as trials need clear criteria, but they must also be as inclusive as possible, representing people from diverse backgrounds so that the approved treatment works for everyone, regardless of race or ethnicity.

Unfortunately, not everyone will be eligible to take part in a clinical trial. People who want to get involved can discuss their options with their GP or healthcare provider- they will be able to help patients make sense of the trial process and guide them through their options.

Lists of clinical trials are published on the Cancer Research UK and ClinicalTrials.gov websites.

Where?

Clinical trials take place across the country, commonly in multiple hospitals at the same time. Trials open in different locations for different reasons, often due to the hospital’s expertise, the facilities available and the number of patients the trial needs to recruit.

The Christie is one of the largest single site cancer hospitals in Europe, treating more than 64,000 patients each year.

More than 500 phase 1-4 clinical trials are active at The Christie.

Trial Spotlight: A trial looking at a drug called UCB4594 for cancer that has spread

Cancer cells evolve clever ways to avoid being detected and destroyed by the body’s immune system. One of these ways is to express a protein called human leukocyte antigen G, or HLA-G. Normally, HLA-G is only found in parts in the body that need protecting from inflammation caused by the immune system.

For example, it is found in cells that make up the cornea and retina in our eyes, and in cells called trophoblasts that form the placenta during pregnancy to prevent the growing foetus from being seen as foreign and attacked by the mother’s immune system.

By expressing HLA-G, cancer cells can evade attack by the body’s immune system, making it a promising anti-cancer target. UCB4594 is a new immunotherapy- a type of drug that stimulates the body’s immune system, designed to target HLA-G. In preclinical testing, it was shown that UCB4594 helped the immune system to identify cancer cells that express HLA-G.

Phase 1 of this trial aims to find a safe and effective dose of UCB4594 in patients that does not cause too many unwanted side effects. Phase 2 will look to see whether UCB4594 works well alone or in combination with other common cancer treatments. HLA-G is expressed in many different cancer types, so this trial is not initially aimed at patients with a specific type of cancer but is open to patients with 1 of 9 different types of solid cancers that have spread.

To find out more about clinical trials, visit the CRUK and the National Cancer Institute websites.