In order to bring therapies to people that address the aging processes, a therapy must successfully demonstrate safety and efficacy in clinical trials.
What are clinical trials?
The definition of a clinical trial is a research study involving people that aims to evaluate a medical, surgical, or behavioral intervention. They are the main way in which researchers discern if a new treatment or device is safe and effective for use in people. Frequently, clinical trials are used to determine if a new treatment is more effective or has less side effects than the current standard treatment.
In the U.S. the Food and Drug Administration (FDA) must approve a trial before it can begin. In order to gain that approval, researchers must conduct laboratory tests and animal studies to ascertain if a potential therapy is safe and effective. Of course, mice are not people, but these tests are a useful basis for moving to clinical trials and should the results be favourable, the FDA will approve the clinical trial.
Clinical trial phases
Clinical trials have a number of phases which all serve differing purposes and are an indication to how progressed they are in terms of reaching use in healthcare.
In drug and therapy development, preclinical studies are a stage of research that begins before human clinical trials can begin, during which critical feasibility, iterative testing, and drug safety data are collected. Preclinical studies are divided into in vitro, in vivo, and in silico studies.
In vitro (Latin for “within the glass”) refers to performing a given procedure in a controlled environment outside of a living organism. Many experiments in cellular biology are conducted outside of organisms using cell lines in cell culture.
A weakness of in vitro experiments is that they do not replicate the exact cellular conditions of an organism. Because of this, in vitro studies may lead to results that do not correspond to what happens in a living organism. It is for this reason that the usual next step of testing is to move to the living system.
In vivo (Latin for “within the living”) refers to experiments within a living organism. Animal studies tend to favor using mice or rats though other animals are sometimes used including flatworms, fruit flies and so on. In vivo testing is better suited for observing the overall effects of an experiment on a living subject and so is normally the step after in vitro testing.
Whilst in vivo studies can offer conclusive insights about the effects of a therapy or disease, there are some ways that these conclusions may be misleading. For example, a therapy could offer a short-term benefit but cause long-term harm. That said, in vivo studies are the cornerstone of translating drugs and therapies to humans.
In silico is an expression used to describe “performed on a computer or via computer simulation.” The expression in silico was first used in public by Pedro Miramontes, a mathematician from National Autonomous University of Mexico, in 1989 in the workshop “Cellular Automata: Theory and Applications” in Los Alamos, New Mexico. During his talk, he used the term to describe biological experiments conducted entirely in a simulated environment on a computer.
While in silico studies represent a relatively new approach, the method’s popularity has risen in recent years and it is now widely used in studies to help predict drug interactions and to help identify drug candidates during assays. In silico studies have great potential and are becoming more refined each passing year, and could help to speed up progress significantly.
The main aim of preclinical studies is to determine the safe dose for translation to humans in preparation for clinical trials and to assess the safety profile of a drug or gene therapy. These tests can also include the evaluation of new medical devices, solutions, and diagnostic tools, as well as drugs and gene therapies.
Phase 0 trial
Phase 1 trials are usually the first type of drug or therapy trial conducted in people. However, sometimes phase 0 trials are conducted before this stage. These studies aim to determine if a drug behaves in the way researchers expect it and follow on from their preclinical studies. Phase 0 studies usually only involve a small number of people and they usually only use a very low dosage of a new drug or therapy. The dose is normally very small but the types of things researchers are interested in here include:
- How a drug or therapy behaves in the body
- Whether the drug or therapy reaches the target
- How target cells in the body respond to a drug or therapy
The main aim of these studies is to help speed up the development of promising new drugs. Testing them in very small doses in humans rather than in animals can also be more reliable and can give scientists useful information more quickly.
Phase 1 trials
Phase 1 studies are usually small trials, recruiting only a few patients. When a new drug or therapy shows promise and might help treat a disease, the Phase 1 trial is often the first step in humans, unless a phase 0 study was conducted of course. Phase 1 trials are launched to find out:
- How much of the drug or therapy is safe to give
- What the side effects are of a drug or therapy
- How the body copes with the drug or therapy
Patients are often recruited quite slowly onto phase 1 trials. So, whilst they do not recruit many patients, they can take a significant time to complete. Sometimes the first group of patients to take part are given a low dose of the drug. If all goes well, the next group will often receive a moderately higher dose. The dose is steadily increased with each group. The researchers monitor the effect of the drug until they find the optimum dose to give; this is called a dose escalation study.
A Phase 1 trial aims to look at doses and side effects and establish the best dosage. This work has to be done before a new drug or therapy can be tested to see if it is effective.
Phase 2 trials
Not all treatments tested in a phase 1 trial reach phase 2 trial. This phase determines whether a drug or therapy works and how effective it is. At this point, a drug or therapy is not presumed to have any therapeutic effect whatsoever. Phase 2 trials aim to find out:
- How well the drug or therapy works
- More about side effects and how to best manage them
- More about the optimal dosage to use
Phase 2 trials are often larger than phase 1 studies. There may be up to 100 or so people enrolled in this phase. Sometimes, in a phase 2 trial, a new treatment is compared with an existing treatment already in use, or with a placebo. Some phase 2 trials are randomised, and the researchers put the people taking part in the treatment groups at random.
A phase 2 trial aims to determine if a drug or therapy is effective, and optionally, to what level compared to other approaches. If the results of phase 2 trials show that a new treatment is as good as an existing treatment, or better, it then moves to phase 3.
Phase 3 trials
These trials compare new treatments with the best currently available treatment. This phase determines a drug or therapy’s therapeutic effect and at this point, the drug or therapy is presumed to have some effect. Phase 3 trials set out to determine:
- How effective a new drug or therapy is versus the current standard treatment
- Different doses or ways of giving a standard treatment
Phase 3 trials usually involve considerably more patients than phases 1 or 2. This is due to differences in success rates potentially being small. So, the trial needs more patients to be able to show the difference. Sometimes phase 3 trials can involve thousands of patients in different hospitals or even multiple countries. Phase 3 trials are almost always randomised, with researchers putting people taking part into treatment groups at random.
A phase 3 trial aims to determine how effective a new drug or therapy is compared to current standard treatments.
Phase 4 trials
Phase 4 trials are conducted after a drug has been shown to work and has been granted a license. The main reasons for running phase 4 trials are to find out:
- More information about the side effects and safety of the drug or therapy
- What the long-term risks and benefits are of the drug or therapy
- How well the drug or therapy works when used more widely
A phase 4 trial aims to refine information about the efficacy or a drug or therapy and study its long-term effects.