Pharmacovigilance

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The pharmacovigilance (drug safety; from Greek  φάρμακον pharmakon "cure poison magic formula" and lat. Vigilantia "vigilance, care") is the ongoing and systematic monitoring of the safety of a drug product for humans or animals with the aim to discover its adverse effects, to assess and understand in order to be able to take appropriate measures to minimize risk . Pharmacovigilance in human medicine is essentially discussed below.

Although already the entire clinical development of a drug in addition to examining the effects desired even the collection and recording of "adverse drug reactions" (UAW, side effects , Eng. ADR ( adverse drug reactions )) includes, but monitoring is a drug from the date of particular importance to its market approval .

At the time of the first authorization , knowledge about the safety of a drug is naturally not complete. Until then, the drug had been clinically tested on a comparatively small number of patients . The patients were also selected for the clinical trial under special criteria and were not representative of the sick population. Rare or very rare undesirable effects and interactions related to drug use usually cannot be detected in clinical studies . However, they are of great importance for the overall evaluation of a new drug. New insights into the safety of drugs can arise long after they have been approved, not least due to the constant advancement in medical science.

A corresponding vigilance system exists for medical devices .

Definition of the WHO

As defined by the World Health Organization (WHO), pharmacovigilance includes:

  • Analysis and defense against drug risks,
  • Activities aimed at the discovery, evaluation, understanding and prevention of adverse effects or other problems related to medicinal products,
  • Risk management , prevention of therapeutic errors, communication of drug information,
  • Promote rational drug therapy .

meaning

Last but not least, the thalidomide tragedy (see also Contergan scandal ) in the 1960s was the reason to establish pharmacovigilance systems in many countries. The legislation of most countries therefore prescribes the systematic collection and evaluation of all incidents (even if they are only suspected cases) that become known when a drug is used widely.

However, the current situation is not entirely satisfactory. Not only is public health affected to a terrifying extent by the occurrence of adverse drug reactions, but also the national economy. Adverse drug reactions lead to a large extent to inpatient admissions or prolong them. They are at the top of the USA's cause of death statistics and produce hundreds of millions of follow-up costs such as B. in Germany or Great Britain. In addition, the topic of drug safety has so far been assigned a very minor role in medical training. Unexpected and undesirable drug effects repeatedly provoke restrictions in the use of drugs or the introduction of certain safety precautions and often result in the entire product being withdrawn from the market .

See also: Market withdrawals due to the disadvantageous risk-benefit ratio .

Recording of adverse drug effects

Spontaneous reporting system

Spontaneous reporting systems are based on the collection of reports about adverse drug reactions by members of the health professions or other people working in the health care system.

In Germany, the system is based on the collection of reports from doctors , dentists , veterinarians or pharmacists received by the drug commissions and pharmaceutical companies to the competent authorities. The spontaneous recording of adverse drug reactions has been anchored in law in the Federal Republic since 1978 as a task of the drug commissions of the medical professional chambers . Doctors are obliged to report suspected adverse drug reactions through their professional code . However, this is often neglected because the side effects are either already known, appear too banal, the doctor considers the causal relationship too uncertain and the reporting procedure is insufficiently known or there is too little time for reporting. The low reporting rates (5–10% or 2–5%), which are also often incorrect, mean that the frequency of occurrence of adverse drug reactions cannot be reliably determined. Critics therefore rate the spontaneous reporting system as it is practiced in Germany as inefficient and call for additional systems to be established.

On the other hand, it is fundamentally advantageous about the spontaneous reporting system that a large basic population is monitored, including groups of people that are mostly excluded in studies, such as children, the elderly and pregnant women. The observation takes place continuously and over the entire range of drugs, the financial outlay is low.

Intensified ADR detection

An intensified recording is carried out by specially trained staff. They are intended to supplement the systems with low reporting frequencies. They study limited populations over a period of time.

Prescription Event Monitoring (PEM)

Prescription Event Monitoring (PEM) is an intensified spontaneous recording program and is used in Great Britain, for example. After a drug is launched, the first 10,000 patients treated are identified and every adverse drug reaction is recorded. Due to the large number of patients, rare side effects (by definition occur in one in 1000 to 10,000 users) are recorded. The prescribing doctors are written to from a central point and report at certain intervals after the first prescription of the drug on the occurrence of any incidents that have occurred since then with the patient in question. The PEM is non-interventional , which means that the doctor is not influenced in the choice of his prescription. The method requires complete prescribing data from the region studied.

National Pharmacovigilance Centers

Usually in addition to the spontaneous reporting system, ADRs can be searched for in a targeted manner, for example in hospital admissions, severe clinical pictures or in specific patient groups (e.g. pregnant and breastfeeding women). In France, a decentralized recording of adverse drug reactions is carried out by 32 " Centers régionaux de Pharmacovigilance ", which are affiliated with universities and hospitals and receive ADR reports from the doctors and nurses working there, but also from doctors in private practice in the region. They are evaluated centrally by the drug agency (" Agence du Medicament "), which maintains a national database. For Germany, the establishment of pharmacovigilance in the course of 12 was AMG - amendment introduced in § 62nd The risk identification and assessment of drugs after their market launch has since been improved through the establishment of a network of regional pharmacovigilance centers. The Swiss pharmacovigilance concept includes the establishment of six regional pharmacovigilance centers, which are tasked with recording and assessing adverse drug reactions and forwarding them to the pharmacovigilance office of the Swiss Agency for Therapeutic Products, Swissmedic .

Controlled studies

Large-scale studies such as controlled epidemiological studies and prospective cohort studies can better quantify the frequency of adverse drug reactions and, in particular, identify unknown drug effects. However, due to the necessarily large number of patients, they are expensive and time-consuming. Pharmacoepidemiological studies that are representative of the population are of considerable importance for the assessment of reports of ADRs, as they are the only way to correctly describe the actual exposure of the population to drugs. Details can be found in the article Pharmacoepidemiology .

Pharmacovigilance in the EU

Legal basis

The legal basis for the establishment of a drug safety system in the EU is the Directive 2001/83 / EC of the European Parliament and of the Council for the creation of a Community code for human medicinal products from 2001. Its revision in 2004 again essentially concerned pharmacovigilance. For pharmaceutical entrepreneurs, this meant that, in addition to the already existing regulations, a detailed description of the intended pharmacovigilance system and a risk monitoring plan had to be submitted with the application for approval of a drug. The guidelines for the practical implementation of EU requirements on the part of pharmaceutical companies , national drug authorities and the European drug agency , including international standards, were revised in 2007 and the final version was published in September 2008 as a separate volume. In 2011, the EU pharmaceutical package for the monitoring of drug risks resulted in new significant changes that were made for EU approvals (through Regulation (EC) No. 726/2004 ) in July 2012 and for national approvals (in Germany around the 16th Amendment to the Medicines Act in October 2012) became legally binding. Guidelines for the most important processes are the (by the European Medicines Agency European Medicines Agency published EMA) and of 16 modules existing Guideline on Good Pharmacovigilance Practices (GMPs) specific.

Work of the authorities

In 2002 the heads of the approval authorities for human and veterinary medicinal products of the EU member states ( Heads of Medicines Agencies , HMA) jointly decided to set up an ad hoc working group to develop strategies for a European risk management system ( European Risk Management Strategy , ERMS) .

A working group of the European Medicines Agency deals in detail with the numerous aspects of drug safety and issues corresponding guidelines. For example, from September 2007, a thorough risk assessment must be carried out beforehand for test drugs that are used for the first time on humans.

Transmission of information, databases

In the EU, pharmaceutical companies are obliged to report reports of adverse drug reactions electronically to their respective competent national higher drug authority. These are forwarded to the European Medicines Agency, which coordinates the uniform recording, collection and evaluation for all EEA member states via the EudraVigilance network and archives it centrally. One database each is maintained for cases from the human and veterinary fields. For the purpose of a uniform classification of the observed adverse drug reactions and a uniform electronic transmission of information, the medical terminology ( MedDRA ) and the transmission format (E2B) were standardized as part of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) .

EudraVigilance is an essential basis for drug safety in Europe, as risks can be identified earlier and better and appropriate measures can be taken based on a standardized and broad database.

Situation in Germany

In implementation of Directive 2001/83 / EC, the German Medicines Act (AMG) obliges pharmaceutical companies to comprehensively document and report all suspected cases of adverse drug reactions (Section 63b AMG). Depending on the severity and regional origin, the suspected cases are to be reported to the competent pharmaceutical authority at short notice (immediately, but at the latest after 15 days) or as part of the submission of regularly updated safety reports (English Periodic Safety Update Report , PSUR), which in accordance with Section 63d AMG in are to be submitted to the drug authorities at the prescribed intervals.

Pharmaceutical consultants are particularly obliged to record notices from doctors about side effects and contraindications or other risks associated with drugs and to forward them to their companies (Section 76 AMG).

Doctors are required by their professional code, but not by law (exception: vaccination complications , see next paragraph) to report side effects and interactions. Pharmacists are obliged to report drug risks in accordance with Section 21 of the Pharmacy Works Regulations and their professional code.

The reporting system for suspected cases of unusual vaccination complications has been regulated in Germany since January 1, 2001 by the Infection Protection Act (IfSG). Since then, doctors, naturopaths and other medical professions have had a statutory reporting obligation : every suspected case must be reported, i. In other words, it is not the reporting person who assesses a possible causal connection, but the competent higher federal authority .

Risk Defense Measures - Pharmacovigilance Procedures

The risk prevention measure in z. B. Germany is the phased plan procedure according to § 63 AMG. At EU level, there is the “procedure for suspending or revoking a marketing authorization” in accordance with Article 31 or 36 of Directive 2001/83 / EC.

In both cases, the pharmaceutical entrepreneurs must be heard before the competent authorities (Germany: Federal Institute for Drugs and Medical Devices , BfArM, or Paul Ehrlich Institute , PEI) or competent bodies (EU: Pharmacovigilance Committee for Risk Assessment of the European Medicines Agency ).

Black triangle

Since September 2013, a black triangle pointing downwards and a short accompanying text have been identifying those medicinal products that are subject to additional pharmacovigilance monitoring. Which includes:

  • all medicinal products approved after January 1, 2011 that contain a new active ingredient,
  • all biological medicinal products authorized after January 1, 2011 such as vaccines, monoclonal antibodies or medicinal products obtained from plasma,
  • Medicinal products for which further data are required after approval or whose approval is subject to certain conditions relating to their safe and effective use.

In April 2013, the European Medicines Agency (EMA) published a first list of medicines under additional monitoring, which is updated monthly. The black triangle can be found in the product information and the package insert / information for use, but not on the packaging.

The background to the labeling is, among other things, the still limited knowledge and experience of the risks associated with new drugs. So far, newly approved drugs or drugs with a special safety profile are not easily recognizable as such. Doctors, pharmacists and patients should use the black triangle to draw their attention to the fact that side effects should be reported, especially with these drugs. The potential side effects of a drug can thus be recognized more quickly.

International cooperation

At the international level there is the WHO Program for International Drug Monitoring , which was founded in 1961 in response to the thalidomide tragedy. It is a network for the collection, archiving and publication of adverse drug reactions in which 110 states officially participate and 30 states as associated members . The center of the reporting system has been the Uppsala Monitoring Center (UMC) of the WHO in Sweden since 1978 . The operated from there "VigiBase" database already contains over 7 million case reports ( case reports ), which received more than 100 countries since 1968 from.

The international societies currently operating that deal with the subject of research on pharmacovigilance at their annual international conferences and with offers of advanced training in this area are the International Society of Pharmacovigilance (ISoP) and the International Society for Pharmacoepidemiology (ISPE).

literature

Web links

Individual evidence

  1. ↑ a b H. Morck: Drug Safety / Pharmacovigilance. 74th Central advanced training event of the Academy for Pharmaceutical Training of the Chamber of Pharmacists Hesse.
  2. ↑ R. Rodríguez-Monguió, MJ Otero, J. Rovira: Assessing the economic impact of adverse drug effects. In: Pharmacoeconomics . 21 (9), 2003, pp. 623-650.
  3. ↑ K. Schmitz, R. Lenssen, M. Rosentreter, D. Groß, A. Eisert: Wide cleft between theory and practice: medical students' perception of their education in patient and medication safety. In: Die Pharmazie - An International Journal of Pharmaceutical Sciences. 70/05, 2015, pp. 351-354. DOI: 10.1691 / ph.2015.4836
  4. ↑ Hannelore Gießen: Pharmacovigilance: Medicines on the test stand. In: Pharmaceutical newspaper . 05/2014.
  5. ↑ AVP special edition “Pharmakovigilanz” of AkdÄ 2005 (PDF; 865 kB).
  6. ↑ Pharmaceutical Newspaper Volume 47, 2003 .
  7. ↑ a b Directive 2001/83 / EC of the European Parliament and the Council on the creation of a Community code for medicinal products for human use (PDF)
  8. ↑ EUDRALEX Volume 9, Pharmacovigilance
  9. ^ European Medicines Agency - Good pharmacovigilance practices .
  10. ↑ List of medicinal products under additional monitoring , EMA list, accessed on November 4, 2019.
  11. ↑ New symbol for drugs under additional surveillance (PDF) Bulletin on drug safety, Issue 1, March 2013, p. 25, accessed on May 8, 2013.