>> In less than a year since the outbreak of the coronavirus pandemic in Europe and Germany, four vaccines – BioNTech/Pfizer, Moderna, AstraZeneca, and most recently Johnson & Johnson – have been approved. All are said to be capable of preventing severe cases of the disease. On the one hand, this is certainly cause for celebration, but also for caution: Can there already be enough, and above all, reliable study results in such a short time, despite the rolling review process used here?
The situation is often presented incompletely to the public. Both the new technology platforms for vaccines developed in recent years and the "rolling review" procedure, in which the European Medicines Agency (EMA) reviews the results of preclinical research and the three phases of clinical trials even before a pharmaceutical manufacturer submits a marketing authorization application, enable accelerated approvals. Furthermore, the conditional marketing authorizations (CMA) granted by the EMA to date for all SARS-CoV-2 vaccines are subject to specific requirements for the marketing authorization holder. In principle, a positive benefit-risk ratio must be demonstrated for each vaccine, and extensive data on efficacy and safety from clinical trials, which are usually not yet complete at the time of approval, must be submitted afterward. The CMA is initially valid for one year and can then be renewed annually. If sufficient data on the benefit-risk ratio are available, a conversion to a standard marketing authorization can then take place. I do not believe the criticism from German health policymakers regarding the slow approval process for the first two messenger RNA (mRNA) vaccines is justified. These approvals were granted only a few weeks after the emergency authorizations for these vaccines in countries such as Great Britain, the USA, and Canada. Furthermore, these conditional approvals also mean that the pharmaceutical manufacturer—unlike with emergency authorizations—is not exempt from administrative and civil liability for its vaccine.

Why this?
Because the results from the decisive
Phase III of clinical trials (comparing the efficacy and safety of the vaccine against a placebo or a vaccine ineffective against SARS-CoV-2) almost always involves interim evaluations, and a final assessment is therefore not yet possible. The "conditional approval" procedure chosen by the EMA is a quite common and regular procedure within the framework of accelerated approvals, which has been used very frequently in recent years, for example in oncology.

Do you expect the "rolling review" process to be used more frequently in the coming years, because it has been learned that this process works?
In the context of vaccine approvals during crises, presumably yes. However, this approval process cannot simply be transferred to new medicines. Various accelerated approval procedures already exist for new medicines in Europe – in addition to the CMA, there is approval under exceptional circumstances, accelerated assessment, and the so-called "PRIORITY" procedure.
The "MEDICINES" procedure (PRIME) is subject to various conditions. A key requirement is the existence of an unmet medical need or that the new drugs are intended for use in crisis situations against a threat to public health. Fortunately, these requirements are rarely met, and I therefore do not expect increased use of the "rolling review" procedure in the coming years.

What is the quality of the respective studies for the currently available vaccines? First: What alternative was used for comparison?
Placebos were used as the comparator arm in both new mRNA vaccines – both BioNTech/Pfizer and Moderna; AstraZeneca's adenoviral vector vaccine was tested against an already approved meningococcal vaccine. This means that the intervention group received the vaccine twice at different intervals, while the control group received a placebo. Furthermore, the development of the AstraZeneca vaccine is based on a different philosophy. The clinical trials were deliberately conducted in different regions of the world (Great Britain, South Africa, Brazil), and the results of these studies are not directly comparable to the results of the two mRNA vaccines, partly due to the emergence of more contagious virus mutations in these countries. In addition, the design of these studies was developed in the academic environment of Oxford University, and the treatment protocol of the four AstraZeneca vaccine trials relevant for approval was not standardized. A smaller group of vaccinated volunteers had accidentally received a lower initial dose of the vaccine, which surprisingly led to better efficacy – possibly because the immune response to the active ingredient used in this vaccine was less pronounced.
The adenovirus was weaker, thus increasing the effect of the second vaccination.

Secondly: How do you assess the state of research in terms of the number of participants?
The number of participants included in each trial is certainly sufficient for the approval studies of a new vaccine. This applies to all vaccines, including those from BioNTech/Pfizer, Moderna, and AstraZeneca, although the four clinical trials for the AstraZeneca vaccine involved fewer participants (just over 25,000). Undoubtedly, the rapid development of these vaccines, which previously took 10-15 years, is a major factor.
This can only be described as a success of science. The fact that it was even possible to test mRNA vaccines, which had never been approved before, in clinical trials within such a short timeframe and then to make them available relatively quickly and in large quantities is very gratifying. This is certainly also due to the fact that scientists have been working on these new generations of vaccines for treating viral infections for several years and have developed new technological platforms for their production.

Thirdly, what about the study designs used for the vaccines approved so far?
All of the above-mentioned vaccines were investigated in randomized controlled trials as part of Phase III. This is a crucial prerequisite for obtaining meaningful results regarding the clinical benefits and risks of these vaccines.

Incidentally, the founders of BioNTech originally wanted to develop a vaccine against cancer.
However, this has not been successful so far. As a hematologist and oncologist, this was not surprising to me. What is particularly important in the context of developing a vaccine against SARS-CoV-2 is that the sequencing of the SARS-CoV-2 spike glycoprotein, crucial for the infection of human cells, was achieved so quickly, namely as early as the beginning of 2020, and that the necessary technology platforms were available to develop the aforementioned mRNA and DNA vaccines. Nevertheless, it would have been interesting if BioNTech had explained in this context why the development of mRNA vaccines against cancer has not been successful to date. This would also have strengthened public confidence in this new technology for producing mRNA vaccines. Certainly, producing an mRNA vaccine against a molecularly well-characterized spike glycoprotein, which is crucial for the infection of human cells with SARS-CoV-2, is not comparable to the complex pathogenesis of cancers, which usually exhibit not one, but multiple genetic alterations.

What are the overall interim results of the approval studies for the Covid-19 vaccines approved so far?
All published Phase III clinical trials relevant for approval have yielded results regarding the efficacy of the three aforementioned vaccines that are generally required for vaccines: 50 percent efficacy or more. This also applies to the AstraZeneca vaccine.

Doctors now face the situation of having to advise their patients on which of the approved vaccines they should take, if they have a choice.
Until recently, the choice of vaccine was limited by the "Recommendations for COVID-19 Vaccination" issued by the Standing Committee on Vaccination (STIKO) at the Robert Koch Institute (RKI), as the AstraZeneca vaccine was initially recommended only for those under 65. This is a highly unusual situation: the AstraZeneca vaccine received conditional approval from the EMA without an age restriction, while STIKO at the RKI issued a vaccination recommendation with an age limit. However, confidence in this vaccine has been undermined by STIKO's age restriction and, more recently, by reports of coagulation disorders (e.g., thrombosis, pulmonary embolism). Naturally, the current safety signals following vaccination with the AstraZeneca vaccine must be carefully analyzed. However, the 22 known cases of thromboembolic complications among the millions of people vaccinated with the AstraZeneca vaccine roughly correspond to the frequency of such complications in the general population, and a causal relationship has not been proven. I myself would also get vaccinated with the AstraZeneca vaccine when it's my turn.

In mid-March, several countries halted vaccinations with the AstraZeneca vaccine. This was due to new reports of blood clots forming in cerebral veins in temporal association with the vaccination. In mid-March, 13 cases of a very rare form of cerebral venous thrombosis, known as sinus vein thrombosis, were reported in Germany. Despite this, the European Medicines Agency (EMA), following a rapid review, continues to recommend the AstraZeneca vaccine. What is your opinion on this latest decision by the EMA? Does it also demonstrate that the conditional approval was entirely justified?
Naturally, these serious adverse reactions that occurred in the EU – both the very rare cerebral blood clots (sinus vein thrombosis), which occurred primarily in women between the ages of 20 and 50 and were sometimes associated with a decrease in blood platelets (thrombocytopenia), and the peripheral vein thromboses, which in isolated cases led to pulmonary embolisms – had to be thoroughly investigated by the EMA's Pharmacovigilance Risk Assessment Committee (PRAC). This investigation has now been completed, and on March 18, 2021, the committee reaffirmed that the benefits of the AstraZeneca vaccine outweigh the risks of adverse reactions. Furthermore, as a risk minimization measure, it was decided to include corresponding warnings in the product information and package leaflet for this vaccine. Furthermore, specific attention was drawn to certain symptoms (e.g., headaches, visual disturbances, arm or leg swelling, shortness of breath) which, if they occur within a period of approximately 7 to 14 days after vaccination, should prompt individuals to consult a doctor immediately.

Did the politicians, did Health Minister Spahn, act correctly when he announced the precautionary suspension of vaccinations?
In my view, policymakers would have been well advised to wait for the EMA's decision and then inform the public accordingly. Given the number of people vaccinated with AstraZeneca in the European Economic Area (approximately 20 million), these are extremely rare side effects, and no evidence of quality defects (e.g., occurrence only in specific batches) has been found.

Which of the approved vaccines do you consider the best?
Most suitable? Knowing full well that they have not been comparatively studied and are also so often the focus of media interest.
Standing effectiveness is of very little significance.
This question cannot be answered definitively due to the aforementioned study designs – there was no direct comparison of the vaccines. It is essential that the person to be vaccinated is thoroughly informed about the advantages and disadvantages of the currently approved vaccines in order to enable an individual decision.

What does 95 percent effectiveness mean?
This figure of efficacy, frequently mentioned in the popular press but unfortunately rarely explained, actually means very little. It refers to relative efficacy, which, for example, in the case of the BioNTech/Pfizer vaccine, is calculated using the following comparison: In the vaccinated intervention group, 8 participants met the predefined criteria for Covid-19; these include, for example, fever, cough, shortness of breath, headache, muscle pain, and loss of taste or smell. In the unvaccinated control group, on the other hand, there were 162 participants who showed symptoms characteristic of Covid-19. The ratio of 8 to 162 results in a relative efficacy of 95 percent. It should be noted that this is based on a total of approximately 36,500 study participants. This figure alone shows that the number of study participants who became ill – the primary endpoint – was low in both groups. Therefore, the underlying figures should always be communicated.

So what do the results of the studies tell us?
Unfortunately, there's not much conclusive evidence. What is certain is that the vaccinations are beneficial, as they have reduced the number of people who developed Covid-19 after infection with SARS-CoV-2 and have also prevented severe cases of Covid-19. However, it remains unclear – since systematic PCR testing of all participants for SARS-CoV-2 infection was not performed – whether participants vaccinated with the BioNTech/Pfizer vaccine reported symptoms such as fever and/or muscle pain less frequently because they considered them side effects of the vaccination rather than symptoms of Covid-19. This could mean that the relative efficacy is less than 95%.

Does this objection apply to all approved Covid-19 vaccines?
For the vaccines approved so far, definitely. For the AstraZeneca vaccine, a combined interim result was calculated – based on interim results from two of the four studies, which recruited a total of 11,636 participants in the UK and Brazil. Depending on the dosage regimen, a relative efficacy of 70 to 90 percent was observed. In my view, however, indirect comparisons of the AstraZeneca vaccine with the results of the mRNA vaccines are inadmissible because the clinical trials included participants in different regions of the world where (e.g., South Africa, Brazil) more contagious virus variants may already have been circulating.

Klaus Cichutek, the president of the Paul Ehrlich Institute (PEI), spoke in this context of the use of a „game changer“.
I wouldn't use that term at the moment: firstly, because of the remaining uncertainties surrounding the vaccines, and secondly, given the rather slow start of the vaccination campaign in Germany. In my opinion, it was unwise on the part of politicians and the Paul Ehrlich Institute (PEI), the federal agency responsible for vaccines, to link such high expectations to the vaccination campaign so early on.

Returning to the conditional approval and the applied "rolling review" procedure: Over time, the pharmaceutical companies bringing the vaccines to market will be required to provide additional data, which will be real-world data including information on side effects, tolerability, and efficacy.
Of course, we urgently need such "real-world data." But first, we need final analyses of the randomized controlled trials. All previous statements about coronavirus vaccines are based on interim analyses of published studies with a median follow-up period of just a few months after the second vaccination. While this timeframe is sufficient to roughly estimate how many participants met the criteria for the primary endpoint—the vaccine's efficacy against a confirmed case of the disease—it is not enough to provide a comprehensive picture of the vaccine's effectiveness against the disease.
(Covid-19) after SARS-CoV infection that began at least 7 days after the second vaccination. Unfortunately, Germany failed to conduct cohort studies during the current vaccination campaign to systematically collect "real-world data" in registries for certain risk groups (e.g., elderly people with underlying health conditions, people with an increased risk of thrombosis, people with diseases or medications that impair the immune system, people with allergies) in order to gain more insights into the efficacy, safety, and immunogenicity of the vaccines in these risk groups. This would have been an important task for health policy, which unfortunately remained inactive in this regard.

Does this mean: Beware of potential bias?
Yes! It's equally important to note that, based on the available data, nothing can be said about long-term safety. We do know, however, that all approved vaccines result in fairly good immunity, both through neutralizing IgG antibodies and cellular immunity—that is, immunity mediated by T lymphocytes. But we know nothing about how immunity behaves after six or even twelve months.

There is data reported in the media that casts doubt on whether immunity will last much longer than six months.
We don't know this for sure due to the short follow-up period in the clinical trials. However, we need reliable data to plan a likely second vaccination campaign in a timely manner. Only a sufficiently long follow-up period will be able to answer this important question. Any potentially delayed side effects could then also be reliably detected. I consider this particularly important given that mRNA vaccines have never been administered before.

The PEI has also launched various safety studies for the active monitoring of vaccine safety and developed the app „SafeVac“ to collect data on the tolerability of Covid-19 vaccines (1).
An app like "SafeVac" is undoubtedly useful. However, it still needs to prove its practicality. Equally important is that physicians consistently report all adverse drug events (AEs) occurring after vaccinations to the relevant institutions, including not only serious AAEs but also suspected cases.

What do the deaths in Norway that occurred after vaccinations tell us?
The documented deaths during vaccination campaigns in Norway should not be overemphasized. In Norway, as in other countries, elderly and frail individuals—who were mostly involved in the reported cases—die for a variety of reasons. Therefore, it is crucial to carefully analyze whether the death was due to natural causes or possibly a consequence of vaccination. The latter is a possibility because frail individuals over 80 years of age with serious underlying health conditions can be acutely vulnerable to systemic vaccine side effects (e.g., fever, vomiting, diarrhea). Fundamentally, the responsible physicians in nursing homes must carefully weigh the options: Despite all precautions, what is more likely for an elderly person (over 80 years old) with serious underlying health conditions: to become infected with SARS-CoV-2 and likely suffer a severe case of COVID-19, or to become seriously ill as a result of severe vaccine side effects?

The problem of dealing with statistical data and communicating it to the public and experts so that they can interpret it correctly is anything but trivial. Is there even a good way to communicate in such a way that the public can develop a truly well-founded willingness to be vaccinated?
In my view, the public communication to date regarding the efficacy and safety of SARS-CoV-2 vaccines has been inadequate. Instead of clearly presenting the aforementioned values used to calculate relative efficacy, the public media and often talk shows have focused extensively on the establishment of vaccination centers, problems with vaccine procurement and administration, and the effectiveness of lockdown measures. I would have preferred a more accessible explanation of what SARS-CoV-2 vaccines are intended to achieve (e.g., sterile immunity in the population), what we currently know about their efficacy and safety, and, above all, which questions remain unanswered. There are interesting publications from the USA, as well as from institutions like the Max Planck Institute for Human Development in Berlin, on how to effectively inform the public. These publications demonstrate how to adequately inform the population about existing uncertainties regarding SARS-CoV-2 vaccinations. When done correctly, people are more willing to accept the currently necessary measures – whether lockdowns or vaccinations.

Who is responsible for this?
I believe that those responsible for health policy in Germany and the experts who regularly appear in the public media should have heeded this open communication about study results on vaccinations more. The clear goal of this communication was, and is, to present the approved vaccines to the public in a way that fosters the highest possible willingness to be vaccinated – always based on reliable and transparent data. In my view, the Institute for Quality and Efficiency in Health Care (IQWiG) should have been more strongly involved in this communication, as it employs experts with extensive experience in the independent, evidence-based benefit assessment of pharmaceuticals and vaccines.

What about the RKI?
The Robert Koch Institute (RKI) undoubtedly employs highly competent virologists and infectious disease specialists. The Standing Committee on Vaccination (STIKO), which is based there, is responsible for the standard recommendations on vaccines, usually published annually in the RKI's Epidemiological Bulletin, and currently primarily for the COVID-19 vaccination recommendations. I believe, however, that the thorough interpretation of clinical trial data on SARS-CoV-2 vaccines and the corresponding communication of that data are not among their core competencies.

Another point is the cost-benefit analysis of the approved vaccines. The original price of the BioNTech/Pfizer vaccine was reportedly quite high at 54 euros per dose.
Yes, this was revealed by a network investigation conducted by ARD and Süddeutsche Zeitung. It was apparently a confidential initial offer to the European Commission. A very informative publication recently appeared in the "Public Health" section of The Lancet (2), showing precisely the prices being paid for SARS-CoV-2 vaccines in so-called "high-income countries"—industrialized nations, including Germany. This includes both approved vaccines and those still in research and development. The lowest price listed was given for each vaccine, which ranged from US$5 to US$30.

However, the initial offer of 54 euros with which BioNTech/Pfizer started the negotiations was a first offer in the price negotiations to the EU.
Absolutely right. I'm bothered that this initial offer was kept secret. And: In retrospect, I consider it unethical compared to what most other vaccine manufacturers charge for a dose.

What should determine the price of a vaccine or a drug?
Primarily, of course, it depends on the actual research and development costs and their financial support by government organizations, but also on the costs of manufacturing the vaccines and the resources needed for the worldwide vaccination campaigns.
ten large volumes of vaccines. With regard to the currently discussed vaccines against SARS-CoV-2, it should also be noted that states have made advance investments. This was important and absolutely correct, because vaccines were and are needed quickly. BioNTech, for example, according to a "Lancet" article (2), received approximately 445 million US dollars in government support – from Germany alone. Other vaccines have also received substantial financial support from national governments and non-profit organizations (such as the Bill & Melinda Gates Foundation and the Coalition for Epidemic Preparedness Innovations, or CEPI). According to the Lancet article, this funding varies considerably, ranging from $3 million from non-profit organizations to $2.1 billion from the US government and the Bill & Melinda Gates Foundation. When one considers that these vaccines will treat not just thousands or tens of thousands of patients, as with conventional medications, but many millions, even billions of people, it quickly becomes clear that the pandemic is generating enormous revenue and thus a significant increase in market capitalization for the leading pharmaceutical companies in vaccine production.

Nevertheless, the costs of vaccinations will still be cheaper than lockdowns, not to mention that they will save countless lives and prevent the long-term effects of COVID-19.
That's why vaccination campaigns were rightly launched worldwide to contain the pandemic. However, we must succeed not only in wealthy nations but also in developing and emerging countries. If we only vaccinate industrialized nations according to the motto "Europe first" or "America first," we will struggle to achieve true herd immunity. In the highly mobile societies we live in today, viruses from outside Europe or America will continue to be introduced, inevitably leading to the emergence of new strains.

They criticized the lack of transparency in pricing and negotiations. Is it possible to conduct such negotiations transparently?
A European initiative, comprising 39 institutions, called early on for transparency in all vaccine procurement agreements. However, it did not call for transparency in price negotiations. While desirable, I consider this rather unrealistic. What could have been made transparent, however, is the scale of the prices and quantities involved, and when and what quantities would be available. This would have given the public a much clearer picture of the real challenges facing a sensible vaccination campaign in Germany. Grand promises benefit no one, least of all those that cannot be kept.

What about the issue of medical disclosure?
This issue is very close to my heart. When I hear what my already vaccinated patients, almost all of whom have malignant diseases, report about the information they received at the vaccination centers, it becomes clear that this form of information, consisting of videos, extensive paperwork, and a brief consultation with the doctor, rarely meets the requirements for thorough medical education that ensures safety and self-determination. I find this unacceptable.

What are you advocating for?
The many people who were recruited at short notice as vaccination doctors cannot possibly know the detailed results of the clinical trials or communicate them in a way that a person willing to be vaccinated can understand. Proper medical information about the SARS-CoV-2 vaccination – especially regarding the efficacy and safety of the vaccines, but also the necessity of vaccination – is best provided in general practitioners' offices. The doctors working there know their patients and their pre-existing and concurrent illnesses and usually know very well how to convey this information so that it is understood.

Professor Ludwig, thank you for the interview.

The interview was conducted by MVF publisher Prof. Dr. Reinhold Roski and MVF editor-in-chief Peter Stegmaier.

Prof. Dr. med. Wolf-Dieter Ludwig

He has been Chairman of the Drug Commission of the German Medical Association since 2006. A specialist in internal medicine, hematology, and internal oncology, with additional qualifications in transfusion medicine, he has been a full member of the Drug Commission since 1999 and a member of its board since 2000. Furthermore, he has been a member of various national and international professional societies since 1988 (including the German Society for Hematology and Oncology, the European Hematology Association, and the American Society of Hematology), and since 2006, he has been co-editor of the independent information bulletin "DER ARZNEIMITTELBRIEF" (The Drug Brief). Since 2010, he has also been a member of the advisory board of "Monitor Versorgungsforschung" (Monitor for Health Services Research). Additionally, since 2013, he has served on the Management Board of the EMA as a representative of the "Standing Committee of European Physicians" (CPME).