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Vaccination (symbol image): "If an approved, effective and safe vaccine is available, the study participants must be informed about it"
Photo: Luis Alvarez / Getty Images
In Grimm's fairy tale "The singing, jumping lion-nape", the daughter of a trader voluntarily surrenders herself to a lion in order to save her father from the beast.
She gives up her freedom for it.
The motive of unselfish renunciation has since been repeated in countless stories - in the coming months it should become very real for thousands of people.
They too may have to ask themselves whether they want to forego something valuable themselves.
And unlike the daughter in the fairy tale, they would not directly protect a relative who is close to them.
You would have to give yourself up to something much more abstract: the greater good.
Three manufacturers of vaccine candidates against the coronavirus have published promising data in the past few weeks that the vaccines could be up to 95 percent effective.
Assessment processes are already underway in Europe and Health Minister Jens Spahn recently raised hopes that vaccinations could be carried out in Germany this year.
Science leads such a quick approval into a dilemma: What happens to the test subjects from the large-scale vaccination studies who did not receive the active ingredient but a placebo without any effect?
Is it ethically justifiable to withhold an effective vaccine from them in order to examine possible long-term consequences in comparison with the control group?
After all: According to the data available so far, only slight to moderate side effects occurred in the vaccination studies, which quickly subsided.
Some test subjects reported tiredness or headaches after the vaccination.
The pandemic is new, the moral dilemma known
"The extent of the pandemic that we are currently experiencing is unique," said medical ethicist Georg Marckmann from the Ludwig Maximilians University in Munich to SPIEGEL.
However, the ethical questions in vaccination studies arise from the basic conflict between research and humans.
The fact that some test subjects receive an active ingredient in large-scale studies and others a placebo is standard in medical research.
In this way, the effectiveness and tolerance can be reliably proven.
In the case of a vaccine, this means that if the vaccinated remain healthy, while subjects from the placebo group fall ill, the agent appears to be effective.
If, on the other hand, the vaccinated get the disease that the substance is supposed to prevent just as often, the vaccination fails.
Ethics committees regulate the conditions under which such studies with placebo groups may take place.
During the ongoing study, the test subjects did not know who got the real drug and who got the placebo.
Only a so-called Data Safety Monitoring Board, or DSMB for short, can find out which subjects are in which group.
This blinding should prevent manipulation.
However, the corona crisis is now confronting science with completely new challenges.
Because several vaccine candidates could already get approval before test series are completely completed.
The European Medicines Agency (EMA), for example, which decides on approvals in the EU, recommends that study participants in the groups assigned to them should be observed for at least another year.
Even if the vaccination is already approved in that period.
"These longer-term data are important to document late side effects and to assess whether the protection against the disease caused by Sars-CoV-2 diminishes over time," it says in a corresponding recommendation.
When are placebo groups ethically acceptable
This could mean that participants in the placebo group will not receive a vaccination in the coming months, even if one were available.
Is that ethical?
"That depends on various factors," explains Marckmann.
How high is the risk for an individual to become infected and become seriously ill?
Would the vaccine actually already be available for those affected?
And does the expected additional gain in knowledge justify the risk for the individual?
"In the case of a drug that shows a high level of effectiveness against a deadly disease in the early stages of the study, it would be ethically more problematic to withhold the drug from patients in the placebo group," says Marckmann.
“It's a little different with a vaccination.
Because it prevents a disease that test subjects are only likely to get. ”However, test subjects would have to be informed about any successes.
"If an approved, effective and safe vaccine is available, the study participants must be informed about it," says Marckmann.
Especially when it comes to risk groups that should be vaccinated first.
Pfizer is already looking for ways to let such participants switch from the placebo group to the study arm with the real vaccine, reports "Nature".
The trade journal cites a corresponding letter to the test subjects.
The manufacturer AstraZeneca also provides in its study protocol to offer participants from the placebo group the real vaccine dose, if this is approved - provided that sufficient doses are available.
How many participants want to change in case of doubt remains to be seen.
"One reason I took part was that, as I understand it, the standard of a blinded study is to unblind if the vaccination proves to be very effective and offer the vaccination to all groups," says one participant from the study with the vaccine candidate from Moderna to »Nature«.
How certain would statements about possible side effects then be?
Assuming that the vaccinated people experience symptoms, one could check in the placebo group whether the same symptoms occur with comparable frequency there.
If so, the vaccination is very likely not the cause.
But what happens if everyone in the study has now been vaccinated?
"Above all, we need a placebo group to determine whether the vaccine is effective or not," says Marckmann.
“Possible side effects can then also be observed after the study is completed.
For example with a vaccination register in which all immunizations and side effects are recorded. "
According to "Nature" there are other ways to adapt the study structure without endangering the test result.
Test subjects who switched from the placebo to the vaccination group could, for example, be evaluated separately.
A similar procedure was used when the first vaccine against shingles was developed.
Companies could also ask subjects to stay in the study, promising to get the vaccine immediately after evaluating the final results.
However, after a vaccine against Covid-19 is approved, science faces another dilemma.
Dozens of other vaccine candidates are still in the running.
However, tens of thousands of participants would be required for critical Phase III studies.
Is it then still ethical to vaccinate the control group with a placebo?
"You do it out of altruism"
Georg Marckmann, LMU Munich
“Actually, one should change the study design and test the new vaccine against the already approved vaccine,” says Marckmann.
"Scientifically well-founded placebo groups would at best be ethically justifiable if the associated risks for the test subjects are low and the approved vaccine is not yet available for the test subjects."
In principle, studies with placebo groups do not have to fail due to a lack of participation, believes Marckmann.
»Again and again, young healthy people volunteer for such studies, even if they themselves do not benefit from it.
You do it out of altruism, «says the medical ethicist.
In fact, one subject from the study with the Biontech vaccine told Nature that he understood the importance of the placebo group and could imagine continuing to participate in the study even if he had not received the vaccine.
A bit like a fairy tale.
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