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Drug safety: there is always a risk

In the best-case scenario, drugs are 100% effective; however, there are many cases where they are ineffective. Medicinal therapy is always associated with numerous risks. Experts from all over Germany recently gathered at the 1st Ulm Drug Safety Day to discuss the mode of action of drugs, the influences on drug action and how drug safety can be ensured. The “Stadthaus” in Ulm, where the meeting was held, was packed.

The meeting, whose particular focus was patients, was organised by the Ulm-based Institute of Naturopathy and Clinical Pharmacology. Many of the speakers called on the patients themselves to take the correct type and dose of drugs and inform their GPs about any other drugs they may be taking, a practice that helps decrease undesired side effects and drug interactions by around a third.

In terms of drug safety, Germany had its fingers severely burnt by the Distaval® disaster. Between 1960 and 1962, Distaval® was used to treat sleeping problems and anxiety. The drug led to severe malformations of the embryo and severe nerve damage in adults. This has meant that since 1978, new drugs must be approved for marketing, and must deliver proof of drug efficacy. Prior to 1978, drugs simply needed to be registered.

The individual situation is decisive

Prof. Julia Kirchheiner is working towards individualised drug therapies. © Ulm University

Drugs have different effects in each person, depending on his/her age and lifestyle, attitude, correct consumption, as well as on his/her genetic background. "Each patient's individual situation is absolutely decisive for a sensible and successful drug therapy," said Julia Kirchheiner, a pharmacologist at Ulm University and a specialist in pharmacogenetics. As organiser of the meeting, Kirchheiner put particular emphasis on the issue of patient safety. She ensured that many of the talks that addressed the question of the different effect of drugs also included a discussion of patient safety.

There is a large number of drugs on the market: although 2,000 would be sufficient for therapeutic purposes, there are nevertheless around 9,000 drugs on the market, of which the majority (81 per cent) are chemical drugs. During the meeting, Kirchheiner talked about the success rate of drugs, pointing out that drugs are often ineffective. For example, only about 25 per cent of anti-cancer drugs are effective, and on average 50 per cent of all drugs are ineffective. Drugs are the fifth most frequent cause of death.

Problematic off-label use for children and youths

Therapies involving drugs are a high-risk process. However, the risk becomes even higher in children and youths, said Jörg Fegert, Medical Director of the Department of Child and Adolescent Psychiatry in Ulm. The prescribing GP also needs to take into consideration the family’s opinion and the fact that many drugs are often not tested for safety and efficacy specifically in children (off-label use). Studies have shown that around 70 per cent of all medications prescribed by paediatricians for the inpatient treatment of children and around 13 per cent of all medications prescribed for the outpatient treatment of children are for off-label indications.

Dangerous drug cocktail

Patients required to take several different drugs face a greater risk of drug interactions and side effects. © University Hospital Ulm

It goes without saying that drugs must be taken correctly and that patients must ensure they follow the instructions. Some drugs such as antibiotics or anti-osteoporosis drugs must not be consumed with milk as this prevents them from being absorbed in the body, with the result that they cannot exert their effect.

In Western Industrial Countries, people over 60 take on average at least 5 different drugs per day, often simultaneously. One third of all medical problems result from interactions between different drugs; the individual drugs inhibit each other and lose their effect, said Angela Seeringer from the Ulm Institute of Naturopathy and Clinical Pharmacology underlining that around 50% of all side effects are preventable.

When onions become dangerous

Some habits affect the concentration and effectiveness of drugs. Uwe Fuhr, a pharmacologist from Cologne, used three examples to show the adverse effects of different habits on the effectiveness of drugs. Drugs used for the treatment of bacterial infections such as ciprofloxacin become phototoxic upon exposure to ultraviolet irradiation and hence make sunbathing a dangerous venture. Food can also influence the effect of drugs; for example, dried and cooked onions, garden sorrel and fresh parsley slow down the effect of blood thinners, which are taken by one in hundred Germans. Fuhr also explained that grapefruit juice can dramatically increase the bioavailability and effect of certain drugs. Grapefruit juice contains a substance which rapidly destroys an enzyme in the intestinal wall, which in turn degrades the drugs.

Plant-based medicines can also be dangerous

Thomas Simmet raised the audience’s awareness of the risks associated with plant-based drugs. © University Hospital Ulm

"Germans have quite a positive attitude towards plant-derived drugs, but it is important to be aware of the fact that plant-based drugs can give rise to the same risks as chemical ones," warned Thomas Simmet, head of the Institute of Naturopathy and Clinical Pharmacology in Ulm. Therefore, plant-based drugs are required to fulfil the same marketing authorisation procedures as chemically produced drugs. Phytopharmaceuticals contain a large number of substances, and, in contrast to chemical drugs, are difficult to produce in identical batches. This can therefore be detrimental in terms of drug safety.

For example, it is possible to produce hawthorn extracts in 864 combinations, said Simmet referring to a study that investigated hawthorn extracts such as "Doppelherz" and came up with "devastating results" (Suzanna M. Zick, Brenda Gillespie, and Keith D. Aaronson: The effect of Crataegus oxycantha special extract WS 1442 on clinical progression in patients with mild to moderate symptoms of heart failure, in: Eur J Heart Fail 2008 10: 587-593; doi:10.1016/j.ejheart.2008.04.008).

The scientist also called for caution in the consumption of the popular St. John's wort, which is often taken to treat mild depression. The herb can have severe consequences for patients with transplants, as it can reduce the concentration of other drugs in the blood, for example the coagulation inhibitor ciclosporin. In the worst case, the consumption of St. John's wort might even lead to the rejection of the transplanted organ. However, plant-based drugs are also known to have positive effects, for example the extract of yew needles, which has an anti-tumour effect.

Side effects – a general risk

Ursula Gundert-Remy from the Drug Commission of German Physicians believes that undesired drug effects are a general risk. The physician quoted a study published in the British Medical Journal, according to which 16,000 deaths are the result of drug side effects, a figure that is higher than traffic fatalities. Five per cent of all hospital admissions are the result of undesired drug effects and Ursula Gundert-Remy believes that around half of all deaths could be prevented, although prevention is not possible in a large number of cases because many undesired drug effects often only occur at a very late stage. Prior to market introduction, clinical studies assessing the side effects of drugs only involve a relatively small number of people, which means that comprehensive knowledge of potential side effects is not available at the time the drug under investigation enters the market.

Safety cannot be measured but it can be felt

Franz Porzsolt, who now works in the field of clinical economics, worked for many years as an internal oncologist and for 20 years he has been searching for an answer to the following question: what can be defined as useful treatment from the patient’s perspective? Porzsolt is not interested in the costs, but in the perceived value a certain type of treatment has for a patient’s quality of life. Porzsolt believes that safety itself cannot be measured, but can only when it is measured against the risk. Porszolt’s thesis: “There must be something like intuitive safety.” He believes if a patient feels that a drug is safe, this is part of the benefit of drug therapy; drugs are expected to be safe, and this gives an added social value, safety is both measurable and can be improved upon. The physician from Ulm referred to studies that show that physicians and patients pursue different goals.

In Germany, the German Federal Institute for Drugs and Medical Devices (BfArM) and the Paul Ehrlich Institute (PEI) monitor drug safety. The authorities intervene if there is a “founded suspicion of unwarranted risks” and they can remove the drug from the market if necessary. Ulrich Hagemann from the BfArM reported on the development of a drug safety network in the European Union, which inspects the quality, harmlessness and effectiveness of drugs. Clear regulations have been put in place with regard to the sale of approved drugs, pharmacy law, pharmacovigilance and advertising. When a drug is approved for sale this effectively means that the approval is a “prohibition subject to authority approval”, said Hagemann.

The central registration offices for drug side effects at the PEI and the BfArM have around 340,000 reports on drug effects on their books; every year they receive around 18,000 to 20,000 reports that are subsequently stored in the European database maintained by the London-based EMEA, reported Hagemann. Authorities and drug producers are required to continuously update benefit and risk assessments of marketed drugs.

Drug manufacturers follow up any suspicions

Petra Kammann, who is in charge of drug safety at Boehringer Ingelheim, confirmed that the company follows up any suspicious cases and pointed out that differentiating between real and apparent risks is a highly skilled job. Once a pharmaceutical substance has received marketing authorisation, the drug manufacturer regularly analyses databases to look for information about new side effects and drug interactions and for the frequency and/or severity of side effects as well as for the side effects in particular patient groups.

Drug manufacturers find out about potential suspicious cases via scientific literature, spontaneous reporting systems and mail or customer service issues. Kammann pointed out that “suspicious cases do not usually alter the risk profile of a certain substance,” but she did express concern that in Germany only around five per cent of side effects are reported, with these reported side effects often being severe ones. Kammann called for the further improvement in the communication between drug manufacturers, experts and patients.

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