In recent months, as the news about the coronavirus vaccine has been pouring in, concepts such as ‘Phase I, II and III’, ‘pharmacovigilance’ or ‘randomized clinical trial’ have crept into the public conversation. In fact, it is not only disputed whether Russia really has the “first coronavirus vaccine“, but numerous vaccines are starting Phase III of their respective clinical trials. In other words, they are on the verge of becoming a reality in pharmacies, hospitals and health centers around the world.
And yet, as a reflection of the central importance that clinical trials have acquired in recent decades, the doubts and feelings found around the ‘race for the vaccine’ are also beginning to become general. It is logical. Although we can find pioneers who applied the scientific method to the search for drugs brilliantly, in the modern world advances around drug safety are often bastard children of medical tragedies.
How do we avoid the next tragedy?
In fact, if we want to understand the birth of the now famous phases of clinical trials we have to travel to the second half of the 20th century. In 1962, when the tragedy of thalidomide, a popular anti-pregnancy nausea drug that turned out to be teratogenic (produced birth defects in fetuses), led to the passage of a series of regulations that forever changed the way research was conducted in biomedicine.
As the cases accumulated, it became clear that at Grunenthal, the company that discovered it, no one had thought it a good idea to do studies with pregnant women before marketing it (not even with pregnant animals). As the victims accumulated in the delivery rooms and the affected platforms mobilized against the company, public opinion began to demand measures to avoid the next tragedy.
In the United States, a legislative package was passed that introduced public oversight and informed consent in clinical trials. It was 1962 and in the following years, the Declaration of Helsinki of the World Medical Association of 64 and the International Covenant on Civil and Political Rights of the UN in 66 established the importance of drug safety and medical ethics at the international level.
Studies, phases and authorizations
Over the years and the increasing ethical and technical demands, biomedical research has had to confront again and again the question that heads this section: how do we avoid the next tragedy? By dint of trial and error, today we have a framework that forces companies and researchers to answer the necessary questions with an adequate level of certainty. This is where the phases of the clinical trial are born and acquire their meaning. This is how medicines and vaccines are tested.
Before reaching human trials, every drug or vaccine has to undergo a series of studies that we usually call ‘preclinical’. Whether in vitro (in the laboratory) or in vivo (with animal models), these studies attempt to extract preliminary data on efficacy, toxicity, and pharmacokinetics. In other words, they are the preliminary studies that help us decide if a specific molecule is promising enough to start the whole ‘clinical’ process.
Phases 0, I and II
Going to human testing is not an easy decision. Clinical trials are usually very expensive, and most of them go nowhere. For this reason, in recent years the so-called “Phase 0” has become popular. These are small human trials in which, using doses of the drug or vaccine at subclinical levels, researchers try to get a more realistic perspective on what the drug does in the body of those who consume it. Be that as it may, with ‘Phase 0’ or without it, if the researchers believe that the drug has possibilities and the numbers support it, ‘Phase I’ would start.
The ‘Phase I’ are trials that seek to assess the safety profile of the drug. In general, they involve small groups of people (between 20 and 100 patients) and try to rule out adverse effects derived from the use of the drug. To do this, the researchers closely monitor the participants: they carefully collect their experience, study the possible symptoms they report and carry out constant analyzes (lately even genetic) to find complications. If you pass this phase and, under normal conditions, up to 70% of the drugs exceed it, Phase II begins.
Phase II continues to review the safety profile (this is new and we need to keep a close eye on it). However, its main objective is to evaluate its effectiveness (and it is about discovering which dose works best); in the case of vaccines, their ability to generate antibodies and how many doses will be necessary. For this, they are usually divided into two sub-phases: the first would focus on demonstrating the clinical efficacy of the product and the second on determining the ideal dose to face Phase III. Under normal conditions, only a third of the drugs that reach Phase II exceed it.
At this point, the most important moment awaits the drug or the vaccine: Phase III. It is where both the Russian vaccine and the different Cansino, Oxford or Moderna vaccines are found. Phase III is key for several reasons: the first is that it is the exact moment when it is tested on a large group of the population. Typically, thousands of people are being randomly inoculated with the still-experimental vaccines under the watchful eye of researchers.
The second is that, in addition to reassessing its efficacy and safety, Phase III allows us to know the real effect of the drug in a real context. Everything that has been done up to this point has been aimed at ensuring that Phase III is safe and has a chance of being successful. But, for practical purposes, it is in this phase that the vaccine or medicine really plays a role. This is so because drugs or vaccines must not only show their efficacy and safety but must come face to face with the “gold standard”, with the best therapeutic option available at that time.
It is difficult and it shows. Only three out of ten drugs manage to overcome this phase because the fact is that it is not enough for a drug (or a vaccine) to be effective against a disease. Hundreds of very promising research projects end up being unable to generate positive effects in clinical practice. The closest example is Ebola: dozens of vaccines and treatments have been discarded even though they seemed effective and safe. Some of them, in fact, have ended up being used for the coronavirus.
They are, as we can imagine, very expensive, very complex and very long trials. With all this in mind, the skepticism aroused by many of the vaccines that are being developed against the coronavirus is well understood. What’s more, it’s understandable why many experts insist over and over that we can’t wait to get a vaccine. Mainly because that could take a long time to come.
Once a pharmaceutical product passes phase III and is placed on the market, Phase IV begins, pharmacovigilance. Drugs are those kinds of things that you can’t stop monitoring. New studies routinely point out possible problems or risks in the use of one or another medicine. This means that medical protocols often change to adapt to the results of this pharmacovigilance. In this Phase, in fact, once it was already on the market when the effects of thalidomide are discovered and enough data accumulated to ban it internationally.
But what happens if we skip these steps?
When Putin announced to have the first coronavirus vaccine, what he was actually doing was skipping Phase III (or, not even that, because, as we noted in the same news item, the vaccine would not be available until 2021 when this phase would already be finalized). The same thing that Beijing did with its military vaccine a few weeks ago. But the problem goes beyond that. If we are strict, without going to the extremes of Russia or China, most of the world’s health authorities have been in favour of making this approval process more flexible with the intention of accelerating the arrival of an effective and safe vaccine.
Here the doubts arise. Does it make sense to skip, to a greater or lesser extent, a process that you are thinking about to ensure the safety of the vaccine? The question is complex, but the answer is simple: this is something that is already being done. In reality, the scheme that we have explained above is a framework with which regulators try to guarantee good drugs. However, the final requirements vary radically depending on the disease we are talking about and the specific characteristics of the drug or vaccine.
If we look at it with perspective, the whole process is a huge scale where risks and benefits are placed: if there are more of the latter than of the former, approval becomes quite probable. When we talk about COVID-19, a new and highly communicable disease that is collapsing the world in an almost unprecedented way, it is reasonable to look for quick solutions that prevent the death of all the people in our power. So the relevant question is not whether or not the processes should be accelerated, but what information we need, what levels of safety we must demand and when it will be worth using which vaccines.
That is the question that health authorities around the world are asking, but if one thing is clear, it is that to find those answers, Phase III is needed in one way or another. Hopefully, they are not mistaken.