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Drug safety and the difficulty of making ends meet

Everybody wants safe drugs – manufacturers, doctors and patients. However, many dangers, both avoidable and unavoidable, make medicinal treatment a high-risk process, despite all best efforts and assertions. Not enough information on drug-related risks is available, and the estimated number of adverse drug reactions that go unreported is quite high.

According to information from the European Commission, 197,000 people in the EU die every year from “adverse drug reactions (ADR)”, a much higher figure than deaths from road accidents, pneumonia or chronic diseases. In Germany, every year around 25,000 people die as the result of interactions between different drugs or adverse reactions to drugs owing to incorrect consumption (Pharmazeut. Zeitung 8th Feb. 2010). Matthias Schrappe of Aktionsbündnis Patientensicherheit (Action on Patient Safety) says that five to ten per cent of all patients (850,000 to 1.7 million) suffer from an undesired event in hospital.

An increasing number of adverse drug reactions have been reported to the BfArM over the last few years. © BfArM

More reported risks than ever

In 2009, the Drug Commission of German Pharmacists (Arzneimittelkommission der Deutschen Apotheker (AMK, 1st Feb. 2010)) received and dealt with 7,400 reported drug risks from German pharmacies, which is the highest figure since 1994. The greatest number of complaints, totalling 30.1 per cent, concern packaging mistakes, followed by undesired adverse drug reactions, misuse reports and galenic deficiencies.

”Drug risks” include everything that can impede drug safety and the harmlessness of drugs. According to the graduated scheme (in German ‘Stufenplan’ - administrative regulations stipulating that authorities must cooperate with drug manufacturers and medical and pharmaceutical associations amongst others) drug risks refer in particular to the following: adverse drug reactions, interactions with other drugs, development of resistance, misuse/incorrect use, habituation/addiction, quality issues (including technical quality), incorrect containers and outer packaging, deficiencies in labelling or in the information on ingredients and use provided on instruction leaflets, as well as drug forgery.

Pharmacovigilance arose from a catastrophe

The thalidomide catastrophe in the 1960s marked the start of pharmacovigilance in industrialised countries. However, in Germany it only became mandatory to report adverse drug reactions from 1978 onwards. The German Medicines Act (AMG) requires the German regulatory authorities compile a centralised register of drug risks and put in place the necessary measures following a graduated plan procedure if required. In Germany, the Federal Institute of Drugs and Medical Products (BfArM) and the Paul Ehrlich Institute (in charge of sera, vaccines, test allergens, test sera, test antigens and blood preparations) are responsible for policing the requirements stipulated by the German Medicines Act.

Adverse drug reactions reported by manufacturers, doctors or pharmacists are investigated, evaluated and stored in a joint database (run by BfArM and AkdÄ, the latter being the German Doctors’ Drug Commission). If a drug is suspected to be the cause of adverse reactions, it is closely observed and if necessary, product information is supplemented with additional warning labels or the authorisation to market the suspect drug is restricted. If the authorities decide to withdraw a drug’s marketing authorisation, which is renewable every five years, the drug must be removed from the market.

According to 2009 BfArM information, drug manufacturers are responsible for reporting hazards related to a medicinal product. © BfArM

Since 1986, the German Medicines Act requires all pharmaceutical companies to have a graduated plan officer who works closely with the German authorities to coordinate the surveillance, collection and assessment of drug risks. In 2004, the German pharmacovigilance guidelines were adapted to European legislation and amended: all pharmaceutical companies are now obliged to provide comprehensive documentation and report possible severe cases of adverse drug reactions. Suspected severe adverse drug reactions must be reported to the authorities within a certain period, and the authorities will then submit the data to the central database of the European Medicines Agency (EMA). Drug manufacturers are also required to present to the authorities up-to-date-reports on the harmlessness of drugs at regular pre-determined intervals.

Granting marketing authorisation is always a compromise

A larger number of adverse drug reactions is reported through intensive monitoring by health professionals than by doctors, dentists and pharmacists’ commissions. © BfArM

It is not surprising that “important safety problems remain undiscovered prior to obtaining marketing authorisation” in one out of five drugs (according to IQWIG (17th Dec. 2009)). When a new drug is launched, it fulfils the minimum standards of safety and efficacy. The granting of marketing authorisation for new drugs is always a compromise: on the one hand, the objective is to provide patients with drugs that are as safe and effective as possible; on the other hand, approval procedures must not take too long so that new drugs can be made available to patients as quickly as possible. For this reason, the regulatory authorities mainly focus on medicinal and pharmacological aspects.

In Europe, there are two alternative procedures for obtaining marketing authorisation for drugs: 1) Under the centralised authorisation procedure, a pharmaceutical company may submit a single application to the European Medicines Agency (EMA) for a marketing authorisation that is valid simultaneously in all EU Member States. 2) In the mutual recognition procedure, a medicine is first authorised in one EU Member State in accordance with the national procedures of that country, and subsequently, the company can seek further marketing authorisation from other EU countries in a procedure in which the countries concerned agree to recognise the validity of the original national marketing authorisation (see: www.hma.eu). Applications for biotechnologically manufactured medicines, cancer and AIDS drugs as well as drugs for the treatment of neurodegenerative diseases have to be cleared under the centralised authorisation procedure. Information about the safety of drugs is incomplete at the time a drug is granted marketing authorisation. The reason for this is that medicines are clinically tested under artificial conditions involving a relatively small number of patients. In addition, these patients are usually selected for different types of clinical testing and do not normally conform to the profile of the average patient treated by general practitioners.

Clinical studies cannot identify rare adverse drug reactions

According to information from the Paul Ehrlich Institute, only around 75% of all 27,716 adverse drug reactions reported were of a severe nature © PEI

Rare or very rare undesired drug effects, interactions with other drugs or other dangers relating to the application of medicines cannot be identified in clinical studies. However, severe, rare adverse drug reactions are of crucial importance when evaluating a new drug. New findings on the safety of medicines, which may depend on new developments in medical science, might emerge long after a drug has received marketing authorisation.

In 2003 in the Berlin Declaration of Pharmacovigilance, several dozens of independent medical journals (International Society of Drug Bulletins, ISDB) found that drug safety has considerable weaknesses and that the process for evaluating and improving the safety of medicine must be reinforced. Since then, “little has changed substantially,” said Wolfgang Becker-Brüser of the journal “arznei-telegramm” (Berlin), which was one of the four German medical journals that worked to drive the Declaration forward.

Deficiencies in pharmacovigilance persist

It was around that period that the drugs Lipobay and Vioxx were withdrawn from the market; now it is the turn of the anti-diabetic drug Avandia, which was withdrawn (at least partially) from the European and American markets in September 2010, although independent researchers had long suspected that the drug was associated with an increased risk of heart attack.

An obvious problem that has frequently been addressed in scientific literature still remains unsolved. In Germany and other countries, the authorities that grant marketing authorisation are usually the same as those that carry out regulatory functions. According to Becker-Brüser, this situation has changed slightly. He points out that the European Medicines Agency (EMA) has been moved from the “Economics” Directorate General to the “Health/Consumer Protection” Directorate General. Nevertheless, Becker-Brüser sees the move as a mere cosmetic correction, because “the same people are still in control”. In addition, EMA and the national medicines authorities are financed mainly through fees charged from pharmaceutical companies. At present, there is no law that stipulates that the budget of medicines authorities should be provided by public funds.

Becker-Brüser also believes that there are considerable problems in terms of transparency in Germany, something that is of vital importance for drug safety experts. He also mentions that the authorities do not grant access to manufacturers’ data as a result of the “rather narrowly interpreted” trade secrets act. The only report that is publicly available is a European evaluation report, which does not mention any sources. Apart from this report, consumers are kept largely in the dark. The American FDA is slightly more transparent than the German and European authorities, as the “freedom of information act” in the USA entitles any member of the public to obtain relevant information on minority votes, for example. However, as Becker-Brüser says, the search for information is fairly time-consuming.

Little research, little information

The ISDB criticises the fact that insufficient information on adverse drug reactions (ADR) is publicly available. Research on drug safety also leaves a lot to be desired, to the extent that the frequency of specific adverse drug reactions (both related to patient and regulatory data) is largely unknown. Becker-Brüser says that the Paul Ehrlich Institute maintains a vaccine database, but he finds it very user-unfriendly to the extent that it is likely to put people off using it.

Becker-Brüser also believes that doctors and pharmacists are not sufficiently motivated to improve pharmacovigilance. Experts rarely report observed adverse drug reactions. The “Drug Commission of the German Medical Association” has recently launched “drug safety mails” (https://www.gesundheitsindustrie-bw.dewww.akdae.de/Arzneimittelsicherheit/UAW-Meldung/index.html) which inform doctors about newly discovered risks. In addition, German pharmacists have recently developed a standardised “Report on adverse drug reactions” (Pharmazeutische Zeitung, 10/2010: Unerwünschte Wirkungen an die AMK melden). One might well ask why this was not done sooner.

The German Ministry of Health has launched an “Action Plan 2010-2012” to promote the safety of medical treatment that is based on a 2008 study carried out by the World Health Organisation on patient safety research. It appears that a lot remains to be done. Many of the measures mentioned in the report are linked to receiving funding.

No reporting system for patients

Patients still receive insufficient, difficult to understand information about adverse drug reactions. Although it is patients themselves who experience adverse drug reactions, established pharmacovigilance institutions and medical authorities do not accept reports directly from patients. There is still no system in place to collect adverse drug reactions reported by patients.

Pharmacoepidemiological research, which is a kind of basic science dealing with drug safety, lacks reliable data from Germany. Although the “Arzneiverordnungsreport” published every year since 1985 by the German statutory health insurance funds provides information on the cost of prescription drugs, the Paul Ehrlich Institute points out that the database used for the report only contains data from representative cross-sectional investigations on the medicines prescribed by selected doctors, and therefore only enables a rough estimate of the medicines actually consumed. No reliable data are available on the extent of “non-compliance”, i.e. the difference between prescribed and actually consumed drugs, and no data at all are available on faulty medications (wrong drug doses that do not take into account a patient’s age and weight).

Important to integrate patients to a greater extent

Many experts believe that as long as the patients’ personal responsibility is not considerably reinforced, one prerequisite for improving drug safety is missing. A small number of investigations on multimedication are nevertheless available. Figures published by the German Drug Testing Institute, which were acquired on behalf of the German Association of Pharmacists, highlight the seriousness of multimedication. These figures show that 25% of all people (around 2.3 million people) insured through a Baden-Württemberg statutory insurance fund were treated with five or more different active compounds in 2009. Eleven per cent of all insured people (940,000) patients were even prescribed as many as eleven or more different drugs (Landesapothekerkammer Baden-Württemberg, 30th June 2010).

Pharmacoepidemiological studies involving German statutory health insurance fund data are mainly restricted to the prescription and quality of drugs. The investigation of rare drug risks, as well as the investigation of drug interactions, requires huge healthcare databases with information relating to a large enough number of people taking these drugs. To date, however, a database relating to the risk monitoring of newly approved drugs or to the investigation of signals of drug risks as part of a spontaneous reporting system is still lacking.

Walter Pytlik - 22.11.2010
© BIOPRO Baden-Württemberg GmbH


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