Database on suspected cases of adverse events following immunisation (AEFI) or serious adverse events following the administration of medicinal products.
- Important notes about these pages
- Special information on the vaccine section of the database
- Adverse drug reactions in clinical trials before the marketing authorisation
- Frequency categories for adverse drug reactions
- Adverse events following immunisation and monitoring of vaccine complications after the marketing authorisation has been granted (surveillance)
- Reports in conformity with the IfSG (German Protection against Infection Act)
- Reporting conforming to the rules of professional responsibility
- Reports pursuant to the Arzneimittelgesetz (AMG, German Medicinal Products Act)
- Evaluation of suspected cases of a vaccine complication and/or adverse effect
- WHO criteria
- Advantages and disadvantages of passive surveillance
- Special information on the sera section of the database
Important notes about these pages
These web pages provide access to information on suspected cases of adverse events following immunisation (AEFI) and serious adverse events following administration of sera (SAE) reported to the Paul-Ehrlich-Institut. The reports refer to prophylactic vaccines and sera for human use which have a marketing authorisation in Germany.
The start page of the database currently contains a section on vaccines and a section on sera. Pursuant to section 4 sub-section 3 of the German Medicinal Products Act (Arzneimittelgesetz, AMG), the term "sera" refers to medicinal products which contain antibodies, antibody fragments, or fusion proteins with a functional antibody component as their active substance and which are used because of this active substance. Sera do not include blood preparations as defined in sub-section 2 or tissue preparations as defined in sub-section 30. Medicinal products categorised as sera include monoclonal antibodies, i.v. immunoglobulins (IVIG) and immunosera.
These web pages provide help and information for interpreting the available data. The SAE database which is publicly accessible is intended to serve both the general public and healthcare professionals.
It is important to consider the following points when viewing the suspected cases of adverse events following the administration of vaccines or sera for human use:
- The data generally relate to reports of suspected cases of adverse events. An event listed in the database refers to a suspected case of an adverse reaction to a medicinal product. Such a suspected case refers to an event which occurred during the period following ingestion or administration of a medicinal product. Thus, the reporting of an adverse reaction does not necessarily mean that the medicinal product is responsible.
- The database contains only those suspected cases which have been reported. Therefore, no conclusion can be drawn as to the frequency and severity of actual cases. Some medicinal products are used more frequently than others. Some types of adverse events may be reported preferentially. The number of suspected cases in the database, which have been reported following ingestion or administration of a medicinal product, therefore does not allow any conclusions to be drawn concerning the actual frequency of adverse reactions to a medicinal product. One suspected case (reported case) may include several adverse reactions, such as fever, headache, seizure.
- In some cases, other medicinal products were administered in addition to the product listed, which may also have caused the adverse event.
- The data require medical interpretation and should by no means be a substitute for information from your physician on the possible adverse events following immunisation or administration of a serum.
- The treating physician is best placed to advise on individual assessments of risk and benefit.
- For reasons of data protection, the cases listed do not identify the patients or the reporting person/institution.
- The information contained in the database will be updated at regular intervals. It is therefore possible that cases have already been reported to the Paul-Ehrlich-Institut but have not yet been included in the database presented here.
- Sera include immunoglobulins which are manufactured from fractionated plasma. The immunoglobulins currently authorised for use in Germany are as safe as blood products, i.e. the risk of virus transmission, such as hepatitis B or C virus or HIV, by such products is extremely low. The viral safety of these medicinal products is essentially ensured by careful selection of blood and plasma donors, extensive testing of the starting material using highly advanced virological methods, as well as efficient virus reduction and inactivation steps during the manufacturing procedure. Suspected cases of viral transmission by the above-mentioned medicinal products are examined carefully by the Paul-Ehrlich-Institut and assessed using various methods including an algorithm (Schosser R, Keller-Stanislawski B, Nübling CM, Löwer J (2001): Causality assessment of suspected virus transmission by human plasma products. Transfusion 41: 1020-1029). No causal relationship between the alleged virus transmission and the administration of an immunoglobulin authorised for use in Germany and manufactured from fractionated plasma has been identified for any of the cases listed in the database.
Special information on the vaccine section of the database
Vaccinations rank among the most effective preventive measures for the protection against infectious diseases. Thus, diseases like diphtheria and polio have been almost completely eradicated in Germany and many other countries as a result of rigorous vaccination programmes. Smallpox has been eradicated world-wide.
Until the start of the 20th century, infectious diseases were considered as the most frequent cause of child mortality. By the turn of the century, approximately 160 children out of 1000 live births still died from an infection such as diphtheria, tetanus, polio, whooping cough (pertussis) or measles by the age of five years. More recent vaccines have contributed to a decline in serious life-threatening infectious diseases in young children.
The same applies to vaccinations for certain groups of adults, as recommended by the Ständige Impfkommission (STIKO) (German Immunisation Commission) at the Robert Koch Institute (e.g. vaccinations against flu [influenza] or tick-borne encephalitis).
In recent years concern over real and alleged risks of vaccines relative to their benefit has grown in many countries including Germany. One reason for this is the fact that most infections that were previously feared have now faded from memory. This situation can be ascribed in part to the success of vaccination.
Thus, very rare or even unproven adverse events have attracted public attention. Declining vaccination rates resulting from these fears may result in a renewed increase of vaccine-preventable diseases.
In the database presented here, the Paul-Ehrlich-Institut has published data on suspected adverse effects which are more serious than the usual accepted list of adverse reactions (suspected vaccine complications, Section 11 IFSG (German Protection against Infection Act)) which have been reported since 1 January 2001 (date of coming into force of the Protection against Infection Act). The database also contains data on suspected cases of severe adverse drug reactions reported to the Paul-Ehrlich-Institut pursuant to Section 63 AMG (Arzneimittelgesetz, German Medicinal Products Act) by the marketing authorisation holder or pharmaceutical company in Germany. The Paul-Ehrlich-Institut also intends to include the earlier data going back to 1 January 1992. Finally, the database also includes reports which the Paul-Ehrlich-Institut received from the Arzneimittelkommissionen der deutschen Ärzteschaft und der Apotheker (Drug Commission of the German Medical Association and Drug Commission of the German Pharmacists), in order to provide a comprehensive overview.
In line with its guiding principles for transparency, the Paul-Ehrlich-Institut intends to give all interested parties the widest access to all relevant data. In doing so, the institute intends to make a major contribution towards improving awareness and facilitating access to information on vaccinations.
Adverse drug reactions in clinical trials before the marketing authorisation
Comprehensive pre-clinical and clinical tests as well as modern manufacturing and testing methods ensure that vaccines marketed nowadays are safe. As a rule, clinical trials performed before granting the marketing authorisation identify the most frequent adverse events and these results are used to evaluate the safety of the product.
Such trials can identify relatively rare adverse events, which occur with a frequency of 1:1,000 – 1:10,000 of all vaccinated individuals. These adverse events will then be included in the summary of product characteristics (SPC) for the vaccine. Only very rare adverse events (<1:10,000) remain unidentified before the marketing authorisation is granted.
Frequency categories for adverse drug reactions
Conforming to European Specifications the following frequency categories are used in the summary of product characteristics:
- Very common (more than or equal to 1/10)
- Common (more than or equal to 1/100 to less than 1/10)
- Uncommon (more than 1/1,000 to less than or equal to 1/100)
- Rare (more than or equal to 1/10,000 to less than or equal to 1/1,000)
- Very rare (less than or equal to 1/10,000)
Therefore, even after comprehensive clinical trials of vaccines, it is possible that very rare adverse events may be observed for the first time during general use of a vaccine. For this reason, it is particularly important to report suspected cases of adverse events and complications following vaccination.
Adverse events following immunisation and monitoring of vaccine complications after the marketing authorisation has been granted (surveillance)
In Germany, the obligation to report suspected cases of vaccine complications and adverse drug reactions is laid down in the relevant laws and rules of professional responsibility (Berufsordnung für Ärzte und Apotheker - professional code of conduct for physicians and pharmacists).
The reporting system described in the following sections is called passive monitoring or surveillance in contrast to the active monitoring of adverse events which occurs during clinical trials and observational studies (after granting the marketing authorisation) etc. (active surveillance).
Results obtained from passive surveillance are not suitable for determining the frequency of a particular adverse effect. Passive reports provide warning signals of risk and the opportunity to react to these signals.
Reports in conformity with the IfSG (German Protection against Infection Act)
Pursuant to Section 6 subsection 3 IfSG, any physician or alternative practitioner is obliged to report an adverse event to the local health authority stating the name of the patient if signs of disease occur after a vaccination for which the vaccination might be responsible and if the adverse event is more serious than the usual vaccine reaction.
Pursuant to Section 11 subsection 2 IfSG, the local health authorities in Germany (Gesundheitsämter) are obliged to transmit the reported suspected cases to the competent federal state authority (Länderbehörden) and the national competent authority, the Paul-Ehrlich-Institut. In keeping with the requirements of data protection, these reports have to be anonymised (personal data must be made unidentifiable).
The Paul-Ehrlich-Institut informs the Robert Koch Institute, which is the German authority responsible for infectious disease control. The Robert Koch Institute performs an epidemiological evaluation pursuant to Section 11, subsection 2 IfSG. After registration in the database, the Paul-Ehrlich-Institut evaluates the reports to identify whether the risk-benefit balance of the respective vaccine has changed, and whether action should be taken, for example pursuant to the AMG (German Medicinal Products Act).
The obligation to report these serious suspected adverse events following immunisation was included in the Protection against Infection Act (IfSG) mainly because it would help to initiate investigations by the local health authority (Gesundheitsamt) to clarify the case.
The individuals concerned shall also receive help from the local health authority.
Which vaccine reactions are not subject to the reporting obligation?
- Temporary local and expected reactions which can be regarded as reactions of the body to the vaccine.
- Signs of disease obviously due to a cause other than the vaccination.
This means that all other suspected cases of vaccine complications are subject to the reporting obligation!
Reporting conforming to the rules of professional responsibility
Pursuant to Section 6 Berufsordnung für Ärzte (professional code of conduct for physicians), a physician is required to notify the Drug Commission of the German Medical Association (Arzneimittelkommission der deutschen Ärzteschaft) of an adverse event that became known to him/her during his/her work. The Drug Commission of the German Medical Association (AkdÄ) is then to transmit the reports received on vaccines to the Paul-Ehrlich-Institut in an anonymised form.
Pursuant to Section 4 Berufsordnung für Apotheker (professional code of conduct for pharmacists) the latter are also obliged to report any suspected cases of adverse drug reactions of medicinal products to the Drug Commission of the German Pharmacists (Arzneimittelkommission der deutschen Apothekerschaft). The Drug Commission of the German Pharmacists is to forward this information to the Paul-Ehrlich-Institut.
Reports pursuant to the Arzneimittelgesetz (AMG, German Medicinal Products Act)
In addition, the pharmaceutical company and/or marketing authorisation holder has comprehensive legal reporting obligations for suspected cases of adverse drug reactions to guarantee that the Paul-Ehrlich-Institut can fulfil its official pharmacovigilance duties. The comprehensive rules governed by the AMG can be found on the internet pages of the Paul-Ehrlich-Institut.
Evaluation of suspected cases of a vaccine complication and/or adverse effect
The Paul-Ehrlich-Institut records in its database all reports of suspected cases of adverse events following immunisation which go beyond the usual vaccine reaction or complication. Each individual report is assessed by a clinical assessor.
To assess the adverse event or vaccine reaction, the following questions must be answered:
- Is the information sufficient to assess the causal relationship between vaccination and the suspected adverse event(s)? If not, will further data need to be requested?
- Are the symptoms recognised in scientific literature as adverse reactions or vaccine complications?
- Are there other vaccines that have shown a similar reaction after administration (analogy)?
- Can the adverse effect(s) be explained scientifically, and is there an immunological mechanism by which the reaction can be explained (biological plausibility)?
- Are there any signs of a batch related increased frequency of suspected vaccine complications?
- Are there other plausible causes for the adverse effects? (previous diseases, adjuvant treatment with medicinal products, international travelling, etc.)
- Is the time interval between the vaccination and the onset of the symptoms plausible? (temporal plausibility)
- Has the vaccine been administered to the patient before, and did the patient tolerate the vaccination at that time?
- Did the same reaction recur after the initial event (with or without re-vaccination)?
In addition, criteria, set up by the World Health Organisation (WHO) are used for evaluating the reactions. The WHO distinguishes between the following reactions and diseases following vaccinations:
- Reactions which are specific for the vaccine.
- Reactions triggered by the vaccine, which, however, could also have occurred spontaneously but for which the vaccine caused the first manifestation of the disease.
- Diseases caused by faulty production, incorrect dosing, or incorrect use of the vaccine.
- Diseases coinciding with but not caused by the vaccination.
In evaluating reports of a vaccine complication and/or adverse effect, it must be borne in mind that the reports concern suspected cases. In view of the large number of vaccine doses administered, diseases may occur in an individual following a vaccination purely by coincidence. However, even these reports are stored in the database, and are therefore contained in the list provided here.
Advantages and disadvantages of passive surveillance
The advantages of recording reports of suspected cases of vaccine complications and adverse events within the passive surveillance include the simultaneous surveillance of all vaccines enabling us to record very rare events. Furthermore, there is no time limit for passive surveillance: reporting, recording and medical assessment are continuous processes.
All vaccinated population groups are included, even those who were not sufficiently represented in clinical trials conducted before the marketing authorisation was granted, such as patients with rare underlying diseases.
A disadvantage of recording reports of suspected adverse events following immunisation is that it is not possible to estimate their actual frequency. We know that not all adverse events are reported. There are various reasons for such "underreporting", for example the patient does not consult his physician, or the physician does not establish the connection with a vaccination (for example because the symptoms are ascribed to an underlying disease).
We cannot put a figure to the exact extent of underreporting. However, serious adverse events are reported more completely than less serious adverse events. Experience has shown that serious adverse events are reported more frequently after administration of a new medicinal product than after administration of a medicinal product which has been on the market for a longer period of time. It can be assumed that taken together, more attention is paid to new medicinal products than to well-established ones.
Another difficulty is that the number of doses actually administered, and therefore, the number of exposed individuals, cannot be accurately identified. We can only obtain approximate figures from the number of vaccine doses in the batches released by the Paul-Ehrlich-Institut and/or the number of vaccine doses sold by the marketing authorisation holder/pharmaceutical company.
Some publications refer to a so-called "reporting rate" as the basis for the frequency of reports of adverse events and/or vaccine complications. However, this also involves some inaccuracies. Only a rough estimate of the reporting rate can be given for suspected cases of adverse events/vaccine complications with regard to the total of the vaccine doses administered, if the number of reports and the number of vaccine doses marketed are used as a basis. The overall reporting rate for 2004 and 2005 calculated by the Paul-Ehrlich-Institut was approximately three suspected cases per 100,000 vaccine doses marketed.
Whether an adverse event is causally linked with a vaccination is particularly difficult to assess. Within the spontaneous recording system, it is impossible to collect comparative data on the spontaneous occurrence of a disease in non-vaccinated individuals.
Taken together, the reporting system for adverse events and vaccine complications is one of the most important early warning systems in the field of pharmacovigilance, despite the limitations discussed above.
The spontaneous reporting system can provide valuable signals of rare and previously unknown adverse events, of an increase in the frequency of known adverse events, of batch-related occurrences of particular adverse events, or of changes in the type and severity of known adverse events.
These signals should be verified using other methods, e.g. controlled clinical studies, post-marketing authorisation safety studies and/or epidemiological studies (case-control studies and cohort studies). To identify signals in a timely manner, it is therefore desirable to report adverse effects which occur in temporal connection with the vaccination, even though there may not be a causal relationship.
Reports of suspected adverse events are also required from a consumer protection point of view, since they provide a good method of recognising previously unknown and/or very rare signals of possible risks of medicinal products.
Based on the evaluation of such possible risks, the Paul-Ehrlich-Institut takes the necessary precautionary measures. The health authority of the respective federal state authority (Länderbehörden) will be involved, if required, to initiate necessary measures falling within its sphere of competence.
Special information on the sera section of the database
Significance and interpretation of the data provided
At the time of granting the marketing authorisation for a novel medicinal product, knowledge of its adverse events is limited to results obtained from clinical trials which can only be performed on a limited number of individuals (patients and, in some cases, healthy subjects). These subjects have been selected for participation in the clinical trial in accordance with specific criteria. Such selection is necessary both to ensure protection of the participants’ health and to increase the validity of the results obtained from the studies.
As a rule, only limited experience has been gained of the broad application of novel medicinal products at the time of granting the marketing authorisation. Furthermore, potential rare adverse events or adverse events which only occur after long-term administration or some time after the medication has been discontinued may still be undetected at the time of granting the marketing authorisation. To detect for instance very rare adverse events as soon as the marketing authorisation is granted, it would be necessary to perform clinical trials on very large patient groups over a longer period of time. This, however, would significantly delay the marketing authorisation and use of innovative medicinal products. Novel medicinal products, however, should be authorised and made available to patients as soon as possible to ensure optimum treatment.
To increase the state of current knowledge which is inevitably limited at the time marketing authorisation is granted, it is important to report events which are suspected to be adverse reactions after the marketing authorisation has been granted ("spontaneous reporting"). In Germany, reporting obligations related to suspected adverse events following the administration of sera are laid down in the relevant legislation ("Arzneimittelgesetz" [German Medicinal Products Act], Regulation (EC) No 726/2004) and the professional codes of conduct for physicians and pharmacists.
Each report of a suspected adverse event is recorded in a database at the Paul-Ehrlich-Institut and assessed medically by a physician.
In this context, please note that the rate of suspected cases of adverse events reported after the marketing authorisation has been granted is of limited value for evaluating the frequency of a particular adverse event. Firstly, not all adverse events are reported. There are various reasons for such “underreporting”; for example, the patient does not report the adverse event to his or her physician, or the physician does not establish a correlation between the symptoms and the administration of the product (for example, because the symptoms are ascribed to an underlying disease). The extent of underreporting cannot be accurately assessed. However, serious adverse events are reported more frequently than adverse events which are not serious. Experience has shown that serious adverse events are reported more frequently after administration of a new medicinal product than after administration of a medicinal product which has been on the market for a longer period of time. Furthermore, it may be assumed that, generally, more attention is given to new medicinal products than to well-established ones.
Another difficulty is that the number of doses actually administered and the number of exposed individuals cannot be accurately determined. In addition, a causal relationship between the medicinal product and the adverse event observed can be demonstrated only in exceptional cases.
Altogether, the reporting system for suspected adverse events is one of the most important early warning systems in the field of pharmacovigilance, despite the limitations discussed above. The spontaneous reporting system can provide valuable signals of rare and previously unknown adverse events, of an increase in the frequency of known adverse events, or of changes in the type and severity of known adverse events. These signals can then be verified using other methods, such as controlled clinical studies, post-marketing authorisation safety studies and/or epidemiological studies (case-control studies and cohort studies). For early signal detection, it is therefore useful and desirable to report all suspected adverse events, not only events where there is an obvious causal relationship between the adverse event and the administration of the medicinal product.
Based on the evaluation of such possible risks, the Paul-Ehrlich-Institut takes the necessary safety measures and steps for risk prevention. If required, the European Medicines Agency (EMA), the competent authority for medicinal products authorised pursuant to Regulation (EC) No 726/2004 EC, will be informed.