Clinical trials are the bedrock of medical research. They are conducted in distinct phases that we will detail in this article. But before clinical trials can even start, it is necessary to conduct preclinical trials.
Those have to test the potential toxicity and efficacy of a drug candidate. They are led either on animals or directly on cells in a laboratory. These studies are crucial to get on with the next stage of the drug development process.
Clinical trials per se are experiments or observations done in clinical research. They are done on human subjects and are designed to answer specific questions about biomedical or behavioural interventions, including new treatments (such as novel vaccines, drugs, dietary choices, dietary supplements, and medical devices) and known interventions that warrant further study and comparison. In short, they allow us to assess whether new drugs (or other types of treatments) are dangerous, how so, and to know the full extent of their effects on the human body.
After preclinical trials have started answering these questions, clinical trials generate data on dosage, safety and efficacy that can be leveraged for humans (as testing a drug on lab mice does not guarantee it will have the same effects in humans).
Clinical trials require health authority/ethics committee approval in the country where approval of the therapy is sought before being able to proceed. These authorities (think of institutions such as the Food and Drug Administration in the United States) are responsible for vetting the risk/benefit ratio of the trial — however, their approval does not mean the therapy is “safe” or even effective, only that the trial may be conducted.
Which makes preclinical testing all the more important to prevent any unforeseen harmful consequences of drug testing. Especially since clinical trials are on average estimated to cost from 44 million dollars (in the genitourinary system therapeutic area) to 115.3 million dollars (in the respiratory system area).
When the estimated development cost of a single drug (including failed drugs and opportunity cost) is around 2.6 billion dollars over a period of 7 to 10 years and the cost for just one patient in a trial is 36.500 dollars, you cannot afford mistakes or wrong leads. In the same vein, very strict rules and protocols are enforced so as to guarantee the patients’ health and safety.
Four distinct phases of clinical trials
The aim of a clinical trial is mainly to produce data on appropriate dosage and potential side effects. The first three phases of a clinical trial especially are focused on those goals. The fourth phase is not necessarily done “in a clinic” per se, it is more of a continued “monitoring of the situation” as more numerous and more diverse patients get treated.
As such, the first three phases are more about answering the question “can the drug actually be used in people?” and the fourth is more about answering the question “are there any other side effects we might have missed despite a thorough investigation?”.
Keep in mind pre-clinical trials should have cleared a lot of the uncertainties surrounding these questions already, but these four phases will provide definitive, actionable data on humans. For a drug candidate to go from each phase to the next, previous trial results have to be validated by national health authorities.
Phase 0
Sometimes, there can be a “phase 0” of clinical trials: it is concerned with pharmacokinetics and pharmacodynamics.
Pharmacodynamics is the study of how a drug affects an organism, whereas pharmacokinetics is the study of how the organism affects the drug. The latter includes “ADME” or “absorption, distribution, metabolism, and excretion”, or studies on how the body processes the drug.
It is also known as the “first-in-human trials”. While this phase may seem very close to preclinical trials, the major difference is that it is done “in humans” (preclinical trials are only performed in laboratories, on cells or animals).
The patients are given subtherapeutic doses (a smaller dosage than required for the drug to achieve the desired effect) to confirm preliminary research before going ahead with the “bulk” of testing.
Phase I
Phase I of a clinical trial describes the experimental treatment on a small (about 20 to 80) test group of usually healthy people.
Except in fringe cases where the drug has a specific interaction with a specific disease and it would do more harm than good in healthy people, take chemotherapy drugs for instance; and even then, it might still be interesting to have a group of healthy people to monitor any other effects.
The point is to gauge safety and side effects as well as to gather data on appropriate dosage.
Phase II
Phase II of a clinical trial sees a larger group (about 100 to 300 people) being tested. And while the first phase was more about safety, now that we have gathered more data on the drug’s dangerousness in humans, we can perform more tests about its effectiveness and dosing requirements.
Phase II is all about testing the drug candidate’s actual effect versus desired or expected effect, usually against a placebo control group (one group is given the drug and the other is given a placebo, to test the drug’s actual effect as accurately as possible).
People with certain diseases are tested to see if the drug “works” or actually has any kind of positive effect. However, safety is still key; and, like with all the other phases, researchers will keep monitoring their patients for side effects (especially on the short-term, as long-term side effects can be monitored more easily with phase IV).
Phase II can last up to several years before national health institutes or other validation institutions give the go-ahead.
Phase III
Phase III of a clinical trial acts as the final confirmation of safety and efficacy before the drug can be used on much larger populations. It is done with the largest groups of patients in test conditions (about 1000 to 3000 people).
On top of gathering ever more precise data about effectiveness, side effects and safety, it is also compared to commonly used treatments and used in combination with other drugs. Validation of phase III means the experimental drug can be marketed.
Phase IV
Phase IV is often misunderstood as yet another “test phase” to see if the drug “works” or is even “safe”.
And while data about safety and efficacy is indeed still being gathered (as biology is still not a science that we know absolutely everything about, like most scientific fields, and given each patient’s unique environment, nor can that possibly be realistic in the foreseeable future), a drug candidate reaching phase IV actually means the drug is safe enough to be released to the public.
Phase IV is thus more about finding out very long-term effects, or niche effects and interactions in very specific cases that could not be tested.
Result and check of clinical studies
Clinical trials are the longest part of a drug discovery process, including extensive data gathering and validation at all stages. They serve to determine the viability of a drug (or a medical device or other form of treatment) in terms of safety, efficiency, etc.
After a clinical trial is completed, the research team then has to analyse all the available information carefully so as not to overlook any potential complications down the line and makes plans if there is any need for further testing. Do keep in mind that the overall success rate of these trials is very low (13.8% overall and 20.9% without oncology, a field that has 3.4% success rate).
But once the data is validated by the research team, health institutions have to then validate it (the FDA in the US for instance). When the results have been reviewed and deemed satisfactory in terms of efficiency and risks, the drug can then be approved for patenting and sale in the country that validated it (the same authorisations for other countries pending review and validation by these other countries’ health institutions, of course).
But it does not stop there: there is a constant post-sale approval monitoring of drugs on the market, so that any previously undetected negative interaction can still be reviewed and the drug’s sale can be suspended.
When it comes to clinical trials, every step of the way is important, from before to after the trials, and that is why this field is so highly regulated and controlled.
