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Off-label use in children: the problem is known but improvement happens step by slow step

The majority of drugs prescribed to children and adolescents have not been specifically licensed for their use. The majority of drugs have been tested and formulated for adults. This so-called off-label practice is associated with greater risks than those one would expect in medicinal therapy. We talked to Michael Kölch, senior consultant in the Department of Paediatric and Adolescent Psychiatry/Psychotherapy (Medical Director: Prof. Jörg Fegert) at Ulm University Hospital about this practice. The 40-year-old medical doctor with special expertise in paediatric and adolescent psychiatry and psychotherapy focuses predominantly on psychopharmacotherapy, psychopharmacoepidemiology and depressive disorders in minors. Kölch is also a specialist in the ethical and legal aspects of these areas.

Many drugs prescribed to children and adolescents have not been approved for their specific use. Studies have shown that 70 per cent of drugs prescribed for hospitalised children and 13 per cent of drugs prescribed for outpatient children have not been licensed for use in children. Are children and adolescents exposed to particular risks?

When children are admitted to hospital it is usually because they are suffering from a serious disease, which is then treated with drugs for specific indications. The majority of the drugs used are not approved for treating children and adolescents. 90 per cent of all drugs given to children in intensive-care wards are not licensed for this purpose. These figures can be expected to decrease in the future because drugs are being more thoroughly tested before marketing authorisation is granted. In the case of a drug that has not been granted marketing authorisation, doctors have no access to the safety data that would exist for a drug that is undergoing the approval process within the framework of systematic follow-up studies, for example.

PD Dr. Michael Kölch, expert in the use of psychopharmaceuticals for the treatment of children and adolescents. © University Hospital Ulm

What are the specificities of the medicinal therapy of children and adults in comparison to adults?

Firstly, the dose of the drug. In pharmacological terms, children between the age of 0 to 18 are divided into five sub-groups: premature babies, newborns, infants, schoolchildren and adolescents. Each of these groups metabolises drugs in a completely different way. In consequence, doctors have to adapt the drug dose to the patient's body weight, by either reducing or increasing the dose of a drug that is normally given to treat the same disease in adults. In addition, numerous physiological processes develop and change as the child grows. For example, in children the blood-brain barrier has not yet reached the adult stage of maturity. This is why some drugs can diffuse into the brain without being filtered. A typical example of this is a drug that is given to adults to treat nausea, which is part of the same substance group as neuroleptic drugs. When given to small children, this drug can lead to severe adverse reactions that do not occur in adults.

With regard to pubertal organisms it is also necessary to take into account the hormonal changes that occur during this period, which leads to drugs having a different binding behaviour and hence generates a broad range of problems. Drugs also metabolise differently in elderly patients who tend to react differently to certain drugs.

What are the major risks associated with medicinal therapies?

One dramatic consequence is that drugs might not be effective at all when given to children. For many drugs, formulations that suit children are not available and medicines adapted to use in children (crushing tablets, suspensions) may lead to problems with dosage and drug absorption. Since a child's body does not behave like that of a small adult, it is not possible to make a simple extrapolation from the adult data. In addition, the long-term consequences of drugs on a maturing organism are unknown. In the field of paediatric and adolescent psychotherapy, it is the brains that stands to suffer most.

How do paediatricians who want to help their young patients handle this situation, when they are aware of the potential risks associated with the medicinal therapy of children with drugs that have only been licensed for adult use?

They do what they have to do, namely treat the children. The granting of a marketing authorisation is, in any case, far from being an absolute guarantee of a drug's safety and actual efficacy. Paediatricians have been aware of this problem for quite some time and are dealing with it in a very conscious way. However, they need to follow off-label practice - there is nothing else they can do. Since a new EU guideline relating to the use of drugs for medicinal therapy in children and young adults has been put in place, there have been greater efforts to test drugs for their efficacy and potential adverse reactions.

What experience have you had relating to this issue in the field of paediatric and adolescent psychiatry/psychotherapy?

In the field of paediatric and adolescent psychiatry/psychotherapy, we sometimes have higher ratios of off-label use than in the field of paediatric medicine. Up to 80 per cent of the drugs we use can be off-label drugs. However, this will soon change. The problem has become very clear, especially in the field of paediatric and adolescent psychiatry: it was discovered in 2004 that studies carried out on the use of antidepressant drugs were worthless with regard to identifying efficacy and adverse reactions, and that the drugs that were available had a lesser effect in children than in adults. Therefore, the data were analysed again and two important results came out of this: age-specific adverse reactions occur in younger adolescents and children. In addition, the majority of antidepressant drugs do not seem to have a great enough effect in children and adolescents.

What is off-label use based on when data are missing? What information can doctors base their decisions on?

The highest priority is to talk to the parents; however, alternative therapies are often not available. Empirical values are available and doctors tend to approximate. It would be completely wrong to talk about therapy decisions as if they were a stab in the dark. Many drugs have been known for a long time. Doctors can therefore rely on individual studies. But such studies must not be mistaken for the clinical studies that are carried out when marketing approval is sought for a certain drug.

Children are not small adults – the EU reacted to this situation by issuing a new directive in 2007. © Pytlik

You have been a core member of the European Medicines Agency (EMA ) board of experts. What is the role of this board?

The members of the Scientific Advisory Group on Psychiatry (SAG-P) provide independent recommendations on scientific or technical matters relating to psychiatry products under evaluation by the EMA's Committee for Medicinal Products for Human Use, including about investigation plans that are needed and also about newly submitted (paediatric) investigation plans (PiP). According to Regulation (EC) 1901/2006 Medicinal Products for Paediatric Use, which came into force in January 2007, it is mandatory for pharmaceutical manufacturers to present paediatric investigation plans when applying for marketing authorisation for a drug. In some cases, studies will be postponed until after studies in adults have been conducted to make sure that research with children is done only when it is safe and ethical to do so. This applies to all indications with the exception of adult diseases such as prostate cancer, or when the risks of a certain drug are regarded as too great for the drug to be given to children and adolescents, and when there is a major ethical concern. With regard to diseases that do not affect children, the requirement for a PiP will therefore be waived (source: EMA).

In all other cases, manufacturers must outline how the company proposes to test the medicine in order to benefit child health and wellbeing. The Scientific Advisory Board advises the EMA whether the data are appropriate and sensible, and which data and studies would be useful.

Is it already possible to draw a preliminary, cautious conclusion?

Yes, it is. The objective of part of the regulation was to strengthen paediatric research networks. The German government had already invested a lot of money in the establishment of clinical study centres, including Paed-Net.

The 7th Framework Programme also funds paediatric studies. The EU supports two large studies in the field of paediatric and adolescent psychiatry, in which researchers from Ulm are involved. The first study is investigating suicidal tendencies in young people taking drugs, including antidepressant drugs; the second study is investigating the approval, efficacy and adverse reactions to drugs used in the treatment of impulse control.

Do you have the impression that the pharmaceutical industry is starting to produce more drugs that are suitable for the treatment of children?

Paediatric studies are far from simple. This is because fewer children suffer from diseases since they are generally healthier than adults. In contrast to what is often said, I do not see ethical problems as the most decisive factor. What is far more difficult is the acquisition of the required case numbers. This is the biggest problem. Whether the reward of extra years of market exclusivity beyond the normal period to which medicinal products are entitled under current EU legislation is an incentive for pharmaceutical companies to turn to a growing extent to drugs for specific use in children remains to be seen; maybe the generics producers find the incentive great enough.

In 2006, the European Commission found that children were underprovided with approved drugs and have issued a new regulation on paediatric medicines with the aim of increasing the development and testing of medicines specifically for use in children. To what extent has this regulation been implemented? Do you think it has led to improvements?

The problem of off-label practice has been known since the 1990s, but it took ten years to discuss it. In 2001, a EU directive was finally issued that has led to the 12th Amendment of the German Medicines Act (AMG). But it will still take some time before improvements can be expected as a result of the regulations that came into force in 2007.

As a clinician, what do you think is the most important problem with regard to using drugs for the treatment of children?

We do not have any reliable efficacy and safety data available on the drugs we are using.

Who finances these studies if the pharmaceutical industry does not believe there are sufficient incentives to carry out such studies?

A mixture of private and public finance. This has become clear from the US experience with a similar law. The EU Framework Programme provides money, the German government finances clinical studies in a specific BMBF priority programme. And we know from the USA that similar legal conditions have led to the approval of more drugs for specific application in children and young adults, and that more knowledge has been generated. In Europe, the regulation will be evaluated within the next few years. This means that improvements can be expected, but this does not mean that the problem is solved.

If a fairy were to grant you a wish, what would it be?

I think I would wish for the acquisition of data and data networks to guarantee safety in patient treatment in the long term. Although these are highly complex to put in place in terms of methods used, this would give us first-hand patient data, in other words data that no normal clinical study can come up with.

The questions were asked by Walter Pytlik, BioRegionUlm.

Further information:

Tan, Jacinta/ Koelch, Michael: The ethics of psychopharmacological research in legal minors, in: Child and Adolescent Psychiatry and Mental Health 2008, 2: 39. doi: 10.1186/1753-2000-2-39

Koelch, Michael/Schnoor, Kathleen/Fegert, Joerg: Ethical issues in psychopharmacology of children and adolescents, in: Current Opinion in Psychiatriy 2008, 21:598-605.

Schubert, S./Lippert, H.D./Fegert, J.M./Kölch, M.: Industrieunabhängige Forschung an Kindern und die 12. Novelle des Arzneimittelgesetzes, in: Monatsschrift Kinderheilkunde 2007, 155: 152-156, doi: 10.1007/s00112-006-1458-5

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