This structured investigation of SmPCs showed that for 72.4% of all indications unambiguous information was available on whether and, if so, from which age or weight an administration in children and adolescents is authorized. For 24.1% of the indications, only ambiguous information, such as the undefined term "children," and for 3.6% of the indications no pediatric-specific information was included in the SmPCs. For medicinal products with marketing authorization before 2007, the proportion of indications with unambiguous information was lower than for medicinal products that were authorized from 2007 onwards, i.e., since the Pediatric Regulation came into force. However, from 2007 onwards, an increase in the proportion of disclosed contraindications for the entire population under 18 years of age was also observed.

4.1 Information Gap on the Authorization of Medicinal Products for Children and Adolescents

With this analysis, we showed that for about 70% of the examined indications unambiguous information was given on age and/or weight for children and adolescents; thus for almost 30% of the indications no or only ambiguous information was given on age and/or weight for children and adolescents. Thus, for more than a quarter of all indications, either decisive information for therapy in pediatrics was missing or it was unclear how to interpret the information.

Despite quality assurance measures such as standard operating procedures, comprehensive data control by pharmaceutical specialists and case-by-case discussions by experts, the assessment of the marketing authorization status was not always possible beyond doubt, due to the vague formulations. The information on use in pediatrics is sometimes not only difficult to find in the SmPCs, but also depends to a large extent on the subjective assessment of the readers, so that different therapeutic decisions cannot be ruled out in practice. Ambiguous formulations such as "should be used with caution" are not helpful for a therapy decision insofar as it remains unclear whether the medicinal product is authorized for children or whether it would be an off-label use. The different definitions of pediatric age specifications also pose a problem [22]. For example, the age specification "children" is not clearly defined in the German Medicinal Products Act [9]. In this regard, an analysis on off-label use in Germany found that it is unclear which age groups are represented by the term "children" at all, and consequently, the term “children” without further specification is not intuitively comprehensible [22]. In addition, the various possible classifications of the age groups under 18 years, for example, "children," "adolescents," are defined differently not only by the different regulatory authorities but also by the professional societies [8]. Accordingly, there is room for interpretation by the readers and this can lead to a risk to the safety of drug therapy. Furthermore, the literature shows that information provided in SmPCs is incomplete and partly contradictory in other patient groups too, so the information deficit does not appear to be limited to pediatrics [11,12,13,14, 23].

Overall, the information gap identified in our analysis is remarkable in that the EMA has required the explicit naming of children and adolescents, including precise age- and weight-related information, in SmPCs since 2009 [7]. The SmPC guideline from 2009 also requires that the full pediatric population is mentioned no matter if the medicinal product is indicated for use in this age group or not [7]. According to our analysis, the implementation of the requirements seems to be only partially successful in the marketing authorization period after 2009, even though the SmPC is reviewed by the responsible regulatory authority as a legal document for the authorization of new medicinal products [7]. Moreover, information on children and adolescents was already required in the previous SmPC guideline from 2005 [24], albeit not to the same extent as in the guideline from 2009. Consequently, information on the pediatric population should have been provided in the SmPCs well before the Pediatric Regulation came into force, and even more so afterwards. Given the lack of information in SmPCs and the associated potential risks for the pediatric population, further measures are desirable. These could include both updating older SmPCs and ensuring that the SmPCs of future authorized medicinal products contain unambiguous age- and/or weight-related pediatric information. In this context, it is worthwhile to consider a study showing that more than 90% of the dosage recommendations of medicinal products authorized in both adults and adolescents were identical for both groups [25]. In addition, an EMA guideline on pharmacokinetics in pediatric drug development issued in 2006 recognizes that dosages for adolescents in particular may be derived from adult dosages if the pharmacokinetic data permit this [26].

Currently, the Pediatric Regulation does not oblige pharmaceutical companies to update the SmPCs or to conduct additional pediatric studies in children and adolescents for already authorized medicinal products. In the absence of a legal obligation or political incentives, it is unlikely that there will be a large-scale update of the SmPCs of those medicinal products in the near future. However, it is desirable that pharmaceutical companies provide evidence from available studies to the public, for example, on their website. This also includes providing further information about safe use as requested by the EMA guideline on the pharmaceutical development of medicines for pediatric use, such as whether a tablet can be crushed or mixed with food or drink [20]. In addition, information about the availability of appropriate dosage forms and the appropriateness of excipients should be provided as the use of inappropriate dosage forms or excipients is frequently avoidable [27]. In the meantime, pediatric-specific drug databases free of charge for the user are valuable sources of evidence-based drug information such as kinderformularium.nl, kinderformularium.de, or the British National Formulary for Children (bnfc.nice.org.uk, free of charge only for healthcare professionals in the United Kingdom).

4.2 Changes in the Provided Information Over Time

Our analysis showed that since the Pediatric Regulation (Regulation (EC) No 1901/2006) came into force in January 2007 [17], the proportion of SmPCs containing unambiguous information has increased for medicinal products with a centralized marketing authorization from 76% before 2007 to 91% in the period thereafter. A similar development could be observed for nationally authorized medicinal products. Overall, the information content for pediatric patients increased since the Pediatric Regulation came into force. The regulation stipulates that pharmaceutical companies must also submit a Pediatric Investigation Plan (PIP) with their marketing authorization application, which must contain information on the planning and implementation of clinical trials in children and adolescents. Since the regulation came into force, both the number of clinical trials for investigating medicinal products in children and adolescents and the number of new marketing authorizations for medicinal products for children and adolescents in the EU have increased [28]. However, most PIPs relate to the authorization of new active substances, less frequently to already authorized medicinal products, which are often used off-label [29]. For national marketing authorizations, the SmPC is also prepared according to the specifications of the "Guideline on summary of product characteristics" [7], but pharmaceutical companies are also provided with numerous reference texts for the authorization of generics that refer to the SmPCs of the originator product [30]. These reference texts partly originate from marketing authorizations prior to 2007, in which the pediatric population was given only little consideration according to the standards at that time.

Furthermore, our analysis shows that while the proportion of unambiguous information for pediatric patients in SmPCs has increased since 2007, the proportion of disclosed contraindications for the entire pediatric population has surprisingly also increased from 35% in the 1997–2001 marketing authorization period to over 51% in the 2017–2021 marketing authorization period. These findings were not expected given our hypothesis of an increased number of pediatric studies due to the Pediatric Regulation. The share of medicinal products with a stated contraindication for the entire pediatric population is high considering that our analysis only included active substances that were considered relevant in pediatrics. This is particularly concerning as there is an increased risk of liability for physicians if they prescribe a medicinal product despite a disclosed contraindication [31]. In summary, the amount of information provided in the SmPC for children and adolescents has increased, but the amount of information on the appropriate treatment of children and adolescents has not.

4.3 Implications on Practice

Our findings indicate a notable deficiency in SmPC information for children and adolescents, which poses a direct threat to the safe treatment of this patient group due to the possible use of incorrect dosages or dosage forms [32]. Especially in pediatric populations, differentiation of dosages according to the age-dependent physiological development is of enormous importance, as pharmacokinetics and pharmacodynamics in children and adolescents are age-dependent [15]. Dosage data cannot be transferred linearly from other pediatric age groups or even from the adult dose to the respective pediatric age group in a weight-adjusted manner [15, 33]. Complex pharmacokinetic considerations are necessary to extrapolate from adults or other pediatric age groups [26], if at all possible. Consequently, incorrect dosages are common in this patient population [34,35,36]. What is more, the off-label use is associated with a considerably increased risk for adverse drug reactions in pediatric patients [32, 37]. Off-label use is one of the most important factors for adverse drug reactions in pediatrics [38].

Despite the urgent need for studies in pediatric patients, there is a lack of research. In a 2019 analysis, it was shown that 12% of the analyzed SmPCs blanket excluded all patients under 18 years of age [39]. The authors concluded that this exclusion cannot always be justified by evidence on age-specific pharmacodynamics or pharmacokinetics, but is predominantly due to a lack of studies [39]. This per se exclusion of the pediatric population can negatively impact the treatment of children and adolescents. Necessary medical prescriptions could be omitted due to the lack of a marketing authorization, or alternatives that are therapeutically less appropriate—but authorized—are used. There is a risk that potentially good therapeutic options may be denied due to a lack of data. This applies especially to the immense number of medicinal products with contraindications for the entire pediatric population. Further investigations are needed to determine why a medicinal product is contraindicated, whether it is due to lack of data or to actual safety concerns, as this has different implications for routine care. This information should be made available in every SmPC.

However, it is important to note that the absence of information on indication or dosage in the SmPCs does not necessarily indicate a complete lack of scientific knowledge. In the past, German courts have acknowledged the existence of evidence-based off-label use [40]. Moreover, a guideline by the German Society of Pediatrics and Adolescent Medicine concludes that off-label use can even be the most appropriate treatment [41]. In routine pediatric care, treatment guidelines are of crucial importance for physicians, as those guidelines efficiently facilitate evidence-based treatment decisions [42]. In contrast, the SmPC is a legal document that does not always reflect the best scientific data available. However, if physicians decide to treat off-label, they are obliged to inform their patients or, in case of pediatric patients, their legal guardians about the off-label use [9]. In addition to informing patients on the benefits and risks of the off-label use, this advice is also legally relevant in order to protect physicians from liability in the event of adverse drug reactions [31]. Thus, the SmPC plays a central role in guiding physicians on the specific limits of off-label use. As a result, physicians are confronted with a dilemma when it comes to making treatment decisions, in which both the demand for evidence-based treatment and liability issues have to be taken into account. However, it is not only about legal consequences: In a survey among physicians treating pediatric patients, more than 80% of physicians reported that it is very important to them to talk to parents about potential adverse drug reactions when a drug is used off-label compared to 38% of physicians who reported this for commonly used authorized drugs [43].

4.4 Strengths and Weaknesses of the Present Study

A limitation of this study is that some of the SmPC texts are based on reference texts or on a standard marketing authorization, and thus congruence between SmPCs of medicinal products with the same active substance could be assumed. The same applies to generic medicinal products for which reference is made to the texts of the original medicinal product. However, it has been shown that the SmPCs of medicinal products with the same active substance can differ considerably in the indications and contraindications stated [44, 45]. Therefore, we decided to analyze all available SmPCs for each active substance, despite potential overlaps or the possibility that the SmPC of a generic product authorized after 2007 refers to an originator product authorized before 2007. In this way, we intended to avoid under-reporting [44, 45].

A strength of the study is the comprehensive investigation of the unambiguity of information on the use of the medicinal products in pediatric patients and the detailed analysis of the information in the SmPCs for each of the listed indications by trained pharmacists. In addition, our analyses are based on more than 8400 SmPCs of 452 different active substances with more than 30,000 indications, covering a large part of the German pharmaceutical market for active substances relevant to pediatrics.