Pharmacotherapy for Children and Adolescents

The study by Neubert et al., published in this issue of Deutsches Ärzteblatt International (1), presents an important quality assurance measure (PaedPharm) for pharmacotherapy in children and adolescents which was developed as part of the KiDSafe project (2).

Major challenge

It is no overstatement to say that pharmacotherapy in children and adolescents is one of the greatest challenges in medicine. This is due to the special developmental physiological features which distinguish children from adults with regard to the pharmacokinetics process of absorption, distribution, metabolism, and excretion as well as the pharmacodynamics of drugs. The lack of approval of many drugs for children is a further contributing factor. Even though there is an evident need for clinical studies to promote the approval of drugs in children, the reasons for their absence are complex. These include, amongst others, their small market share and the pharmaceutical challenge they pose.

Status Quo

Unfortunately, even higher-level strategies for solving the problem have not led to any significant improvement in the situation, for instance, the European Pediatric Regulation with its key components, namely, the Pediatric Committee, pediatric investigation plans, and the pediatric-use marketing authorization (PUMA) (3).

Thus, depending on the particular study, between 42 and 90 percent of children and adolescents in the inpatient sector and between 46 and 64 percent in the outpatient sector are prescribed drugs off-label (4, 5). Although the use of drugs off-label is often unavoidable, it is associated with considerable risks for the children being treated (for example, unexpected adverse events [ADEs], medication errors [ME]) as well as for the doctor treating them (for example, responsibility for the proper prescribing, possible lack of funding by the statutory health insurance funds) (3). Medication errors can arise during the prescription, preparation, delivery, or administration of a drug. The absence of dosage forms appropriate for children often calls for manipulations to be made, i.e., changes to the dosage form prior to administration, which are not entirely harmless (3). The not inconsiderable number of drug prescriptions per child per year ranges between 0.8 and 3.2 (4).

Study modules

The key modules of PaedPharm, which were developed as part of the KiDSafe project, are:

• a digital pediatric drug information system (PaedAMIS),

• pediatric pharmaceutical quality circles (PaedZirk), and

• a national adverse drug event and medication error reporting system (PaedReport).

In their cluster-randomized trial, the authors revealed a reduction of ADE-related hospitalizations in 12 regions in Germany from 4.1% under control conditions to 3.1% under intervention conditions. Even though the results were not statistically significant, they cannot be stressed highly enough against the background of over 5000 analyzed admissions and a relative risk reduction of around 26%. Particularly worthy of mention is the digital pediatric drug information system PaedAMIS, which is freely available at a very low threshold under the name kinderformularium.de. More than 570 evidence-based monographs on drugs for use in children and adolescents are to be found there (data status: 5–2023).

Results of the secondary analysis

A secondary data analysis undertaken as part of the KiDSafe project showed that, of 33 serious adverse events resulting in extended hospital stays for the patients, 22 hospitalizations could have been prevented by using PaedAMIS. This would have saved 620 days in hospital and about 240 000 euros (2). This effect is highly relevant in times of limited financial resources with insufficient numbers of inpatient beds across pediatric and adolescent medicine. That is why the continuous further development and ongoing updating of the digital pediatric drug database kinderformularium.de are essential.

Between desire and reality

The pediatric pharmaceutical quality circles were highly appreciated by the doctors participating in the study, and the ADE reporting rate was increased by a factor of five. It therefore seems reasonable, and is in line with the wish of those involved in KiDSafe, to establish a central point of contact for the needs of pharmacotherapy in children and adolescents, similar to the contact point for drugs during pregnancy (Pharmacovigilance and Advisory Center for Developmental Toxicology, www.embryotox.de) (2). Such a center for pediatric pharmacotherapy could serve as a link for international cooperation (2) and also convey aspects of health services research in this area into the outpatient sector. It is therefore regrettable that the Innovation Committee at the Federal Joint Committee has not recommended adoption of the KiDSafe project into standard care (6), even though the study results were positive throughout, albeit with no statistical significance (see above). The authors discuss in detail the possible reasons for the lack of statistical significance. It should be stressed that the overriding positive general message of the study is underlined by the German Society for Pediatric and Adolescent Medicine (DGKJ) and the Professional Association of Pediatric and Adolescent Physicians (bvkj) in a joint statement on the negative decision of the Innovation Committee (6).

The fact that further measures to improve pharmacotherapy for children and adolescents are urgently needed remains undisputed.

Establishing PaedZirk on a nationwide basis would therefore have the potential to create awareness for the problem, to provide content training, and to optimize intercommunication as well as with patients and custodians. Information systems (PaedAmis) make the prescribing of medicines easier and could be electronically supported in the future (computerized physician order entry [CPOE]) and supplemented with clinical decision supports [CDS] (7).

In the end, all those who write out prescriptions for children and adolescents should maintain their awareness of the problem that they are not dealing with “small adults”.