Posted on Apr 15, 2021, 11:10 AM
The very rare but serious cases of thrombosis caused by the AstraZeneca vaccine have cast doubt, in the minds of some, on the quality of this product. To convince the most reluctant to vaccinate with this one, the health authorities boast a very favorable benefit / risk balance.
Beyond vaccines, this relationship between therapeutic effects and undesirable effects is the basis of whether or not all health products are authorized to be placed on the market. In France, the National Agency for Medicines and Health Products Safety (ANSM) issues marketing authorizations (AMU) after evaluation of this balance. For this, it has data transmitted by laboratories, as well as opinions issued by international health agencies such as the European Medicines Agency (EMA) and the World Health Organization (WHO).
1) What do we mean by “benefits” and “risks” in pharmacies?
The expected benefits of a health product are all the positive therapeutic effects it induces. “It can be a matter of treating an illness, but also of alleviating a symptom, improving the patient’s comfort of life” or, in the case of vaccines, for example, of protecting him against a disease, explains Arnaud. Bruckert, doctor of pharmacy and author of “The benefit-risk balance of drugs”.
Conversely, risks refer to all the undesirable side effects. “Whatever the drug or vaccine, there are risks,” says Arnaud Bruckert. Only health considerations come into play. The cost of the drug is also assessed and is based, in the context of reimbursed drugs in particular, on a political and economic choice as well as a health one.
2) What are the specificities of the evaluation of the benefits and risks of vaccines?
The evaluation of the benefit / risk balance for vaccines has specific features because the challenge is not to treat a disease, but to protect both an individual and a population against it. “In the benefits of vaccines, there is an indirect effect, since the vaccination of a fairly large group also protects individuals who are not vaccinated,” adds Arnaud Bruckert. “For some types of virus, we can achieve ‘herd immunity’, that is to say the threshold at which an epidemic is extinguished,” he adds. Thus, thanks to a long and massive global vaccination campaign, smallpox was declared eradicated in 1980.
Another specificity, “we will administer a vaccine prophylactically, in anticipation of a disease, so we inject it into a healthy person,” said Arnaud Bruckert. “We know that the Covid is transmitted very quickly, so we have a good chance of catching it, but there are other diseases where this is not or no longer the case,” he explains. The expected benefit is higher if the incidence of the disease is high, and vice versa.
“For vaccines, it is easier to determine the societal benefits because, according to epidemiological data such as incidence, the rate of hospitalization and the rate of death can be easily calculated before and after vaccination”, underlines Arnaud Bruckert. Contaminations are certainly hypothetical, but the incidence allows us to put this probability beforehand. The example of Israel, a country with the highest vaccination rate, or the comparison in France between AP-HP staff, vaccinated as a priority, and the rest of the Ile-de-France population make it possible to measure the real benefits of the vaccine.
3) To what extent is a benefit considered sufficiently important to tolerate a risk-taking?
This question is both the most central and the most complex. “For a large part of health products, it is quite easy,” notes Arnaud Bruckert. If you have a medicine that is supposed to treat a headache and the side effects are extremely serious, this medicine will not be allowed. It is the same when a drug, conversely, presents only very weak and / or very rare undesirable effects whereas it cures a fatal disease.
“On the other hand, it is more complicated for health products which provide very significant benefits but with significant risks”, explains Arnaud Bruckert. “Today, it is done implicitly and qualitatively,” he describes, essentially based on debates between experts. Other criteria are also taken into account, such as the existence or not of alternative treatments with a more favorable benefit / risk balance, as well as the means of preventing or treating any undesirable effects.
4) When and by whom is the risk / benefit balance assessed?
The scale is evaluated many times, from the design of the health product – drug or vaccine – to monitoring safety signals after a possible withdrawal from the market, through the phases of clinical trials and marketing. The evaluation is made, throughout the life cycle of the drug, both by laboratories and health authorities.
The benefit / risk balance changes over time, as knowledge of these benefits and risks of the product and of the disease progresses. The management of a disease may also change or new products may reduce the benefits of the product being evaluated.
The benefits and risks are calculated during the clinical trial phases by comparing a treated group (animals then humans) and a placebo group. The benefits can then be reassessed, particularly in the face of the arrival of a new, more effective product or the evolution of a disease (with the mutation of a virus, for example). This has, for example, pushed France to no longer inject the AstraZeneca vaccine in Moselle, because it is deemed to be less effective against the “Brazilian” variant of Covid-19 than its competitors Pfizer and Moderna.
On the risk side, they are continuously assessed through pharmacovigilance. Doctors and patients alike are encouraged to report any side effects they encounter. The discovery of a greater proportion of a disease or symptom in the treated population than in the general population – the formation of thromboses in the case of the Covid-19 vaccine, for example – may lead to the withdrawal of market a product or revise its administration conditions.
5) Is it possible to precisely quantify the benefit / risk balance?
A strictly quantitative evaluation of the benefit / risk balance is not enough, and the interpretation of this balance also takes ethical criteria into account. If we know that a health product will be responsible for the death of one in a million patients treated, to what extent will this death be considered acceptable in the face of 999,999 lives saved? From what ratio can the benefit / risk balance be considered “favorable”: 1% of deaths? 1 in 10,000? 1 in 1 million? The answer is obvious: “It depends. “
Researchers at the Winton Center at Cambridge University attempted to take this quantitative approach to the AstraZeneca vaccine, and their study highlights these difficulties. They decided to compare the number of intensive care admissions avoided in sixteen weeks in the face of cases of blood clots for a population of 100,000 people. They thus presented three graphs according to whether the risk of exposure is low, medium or high. Here is the average scenario, with a daily incidence of 6 per 10,000:
This graph shows in a synthetic and meaningful way the balance, which tilts very clearly on the side of the profits for the 60-69 years, but which seems much more balanced for the youngest.
The balance changes depending on the incidence: 31 intensive care admissions are avoided for 0.4 cases of blood clots in 50-59 year olds moderately exposed to the virus. Only 10.5 ICU admissions are avoided if the incidence is lower (2 cases per 10,000), but significantly more (95.6) are avoided if the incidence is high (20 cases per 10,000):
However, the researchers say, these visualizations have many limitations. They do not show that the benefits of the vaccine are cumulative throughout the period when the patient is immunized, while the risk in question was only observed near the date of the injection. In addition, not all the risks associated with Covid-19, such as long Covids, are taken into account, nor all those of the vaccine, such as allergic reactions. Thus, admit the researchers, “all of these factors make any decision about the Astra-Zeneca vaccine complex.”