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The Summary of Product Characteristics (SmPC) is required to provide unambiguous information on the authorized use of a medicinal product. Therefore, we performed a structured analysis of the information provided for pediatric patients in current SmPCs.
Methods
In the German SmPC of the medicinal products of 452 active substances, we analyzed for each of the listed indications whether information on pediatric use was available in Sects. 4.1–4.4 of the SmPC and, if so, whether it was unambiguous. Information was considered unambiguous if it indicated an exact age- or weight-related specification. The analysis also considered the type of marketing authorization and the date of marketing authorization, either before or after the Pediatric Regulation 2007 came into force.
Results
Among the 30,354 identified indications in 8464 SmPCs, unambiguous information was found for 72.4% (21,974/30,354) of the indications. Of these, 45.4% (9967/21,974) disclosed a contraindication for the entire population under 18 years of age. The proportion of unambiguous information was higher for medicinal products with centralized marketing authorization (86.5% [1449/1676]) than for those with a national one (71.6% [20,525/28,678]; p < 0.001). A higher proportion of unambiguous information was found for the marketing authorization period 2007–2021 compared with 1996–2006 (1996–2006: 63.8% [7466/11,694]; 2007–2021: 82.1% [12,349/15,040]; p < 0.001).
Conclusion
For about a quarter of all indications, no or only ambiguous information was available for pediatric patients. The measures initiated in recent years to increase pediatric-specific information in SmPCs should be intensified in order to improve drug safety in children and adolescents.
Markus Herzig and Simone Eisenhofer share first authorship.
Key Points
For more than a quarter of the indications examined, there was no or only ambiguous information available on the authorized use of the medicinal product in pediatric patients in the Summaries of Product Characteristics (SmPCs).
Almost half of the indications with unambiguous information excluded use for all pediatric age groups.
Consequently, an increase of specific information provided in the SmPCs for the use of medicinal products in pediatrics is urgently needed to improve patient safety in children and adolescents.
1 Introduction
Off-label use is defined as the use of a medicinal product other than as authorized by the regulatory authorities [1‐3]. In pediatrics, off-label use is common [4‐6]. Information on whether a medicinal product is authorized for a specific age group can be found in the respective Summary of Product Characteristics (SmPC) [7]. Thus, the SmPC is an important basis for deciding whether an administration is within the scope of the marketing authorization or off-label. However, the definitions of off-label use by the regulatory authorities that approve these SmPCs are not completely congruent [1‐3]. The classification of pediatric age groups is also heterogeneous in some areas. In particular, the term "children" is used differently in pediatrics, as there is no uniform definition of this age group [8]. For example, the World Health Organization defines “children” as aged from 1 to 12 years, with further subcategories [8]. The German Medicinal Products Act distinguishes in Article 10 the patient populations "babies, children and adults" without further specifications [9]. To eliminate inconsistencies, the European Medicines Agency (EMA) as well as the US Food and Drug Administration (FDA) implemented the definition of the age group of children as being from 2 to 11 years according to the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use in the year 2018 [10]. However, especially in medicinal products authorized prior to the implementation of this guideline, a heterogeneous use of the term “children” can be observed. In addition, the specifications in the SmPCs are often compromised by unclear formulations with regard to the listed indications, missing information on dosages for special populations, or imprecise statements such as "Not recommended for children" [11‐14]. Overall, this carries a high risk of individual (mis)interpretation of the authorized use of a medicinal product. Therefore, it is of utmost importance to provide clear age and weight specifications in the SmPCs, as the pharmacokinetics and pharmacodynamics in the pediatric population are age-dependent [15], and the determination of standardized drug half-lives is challenging in pediatrics [16].
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Quantitative analyses on the unambiguity of information on the use in children and adolescents provided in the SmPCs of medicinal products used in pediatrics are scant. There is also a lack of data on whether this information content differs between the SmPCs of centrally and nationally authorized medicinal products, and whether the information content improved after the Pediatric Regulation came into force in 2007. The Pediatric Regulation aims to increase the number of clinical trials and authorized medicinal products in pediatrics and to improve the availability of information for use in children and adolescents [17].
We therefore conducted a structured analysis of the information available in current SmPCs for pediatric patients in order to comprehensively investigate the unambiguity of the age- and weight-related specifications made in the SmPCs for pediatrics, and to evaluate possible changes in the provided information over time.
2 Methods
2.1 Study Design
In the period from January to November 2021, the SmPCs valid at the time of the study of 452 active substances used in the German pediatric population were analyzed (see Online Supplementary Material (OSM) Table 1). According to Article 2 of the Pediatric Regulation, the pediatric population comprises the part of the population between birth and 18 years of age [17]. Therefore, the data provided for this age group in the SmPCs were included in the analyses. The analyses were based on the EMA definition of off-label use, which defines the use of a medicinal product in an unauthorized indication, age group, dosage, or route of administration as off-label use [1].
2.2 Data Collection Process
An expert panel of pediatricians and clinical pharmacists compiled and prioritized a list of 452 active substances for the investigation. The choice of active substances was based on an analysis of health insurance data on prescribed medicinal products in pediatrics [18]. This initial compilation was modified by the experts in a structured consensus process. The selection criteria included, in particular, the prescription frequency, the potential for problems with dosing and other drug-related problems in pediatrics, as well as the potential for serious adverse drug reactions.
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We identified all medicinal products on the German market at the time of the investigation that contain the previously defined active substances using the ABDA database (ABDATA, Pharma-Daten-Service; Eschborn, Germany). The ABDA database offers comprehensive information and facts on medicinal products in Germany, including current SmPCs. The database is updated every 14 days to ensure accuracy. The corresponding SmPCs were searched both in the ABDA database and, if not available there, in the following databases: PharmNet.Bund Arzneimittel-Informationssystem (Federal Institute for Drugs and Medical Devices; Cologne, Germany, and Paul Ehrlich Institut; Langen, Germany), online database of the EMA (European Medicines Agency; Amsterdam, The Netherlands), Gelbe Liste Online (Vidal MMI Germany GmbH; Langen, Germany), Fachinfo-Service (Rote Liste Service GmbH; Frankfurt/Main, Germany). If none of the databases contained a respective SmPC, we attempted to obtain the SmPC directly from the marketing authorization holder. We used the definition of “medicinal product” according to Article 1 of Directive 2001/83/EC [19], which is also referred to in the EMA Guideline on the pharmaceutical development of medicines for pediatric use [20].
For each SmPC, the following data on the medicinal product were recorded: Trade name, active substance, Anatomical Therapeutic Chemical (ATC) code, year of authorization, and date of the SmPC. Subsequently, all indications listed in the SmPC were identified (SmPC section 4.1) and the respective information for use in children and adolescents was extracted from SmPC Sects. 4.1, 4.2, 4.3 and 4.4. (Therapeutic indications, Posology and method of administration, Contraindications, and Special warnings and precautions for use). In addition, data from clinical studies with pediatric patients were collected from Sect. 5 (Pharmacological properties), which can be used as a guide for therapy decisions in the absence of information in Sects. 4.1–4.4.
If a SmPC covered several medicinal products, for example, different strengths or dosage forms, the SmPC was evaluated separately for each medicinal product and the specific information related to it.
2.3 Data Classification
The information extracted from Sects. 4.1–4.4 was classified as "unambiguous," "ambiguous," and, if no information was available, "no mention of children/adolescents." The boundaries of unambiguity were defined by expert consensus of clinical pharmacists and pediatricians. Exact age- or weight-based specifications and the specification "children and adolescents," as this includes the entire pediatric population, were considered "unambiguous." Statements to "use with caution," phrases with the word "should" or the word "children" without further age or weight reference were rated as "ambiguous" (Table 1). For further analysis, the formulations with unambiguous information were categorized according to whether a contraindication was disclosed for the whole pediatric population or whether pediatric-specific information was provided, such as dosages for specific pediatric age groups.
Table 1
Examples of wording in Summary of Product Characteristics (SmPC) and their unambiguity rating in Sects. 4.1, 4.2, 4.3 and 4.4 (Therapeutic indications, Posology and method of administration, Contraindications, and Special warnings and precautions for use)
Section of SmPC
Example from SmPC
Unambiguity rating
4.1
Authorized from [...] years of age
Unambiguous
4.1
For use in children and adolescents from a weight of [...] kg
Unambiguous
4.1
Use in children and adolescents only with caution
Ambiguous
4.1
Not authorized for children
Ambiguous
4.2
Adults and adolescents from [...] years of age
Unambiguous
4.2
In children, half the adult dosage should be administered
Ambiguous
4.3
Should not be used in children under [...] years of age
Ambiguous
4.3
Must not be used in children under [...] years of age
Unambiguous
4.3
Use in children under [...] years of age: contraindicated
Unambiguous
4.3
Not for use in children
Ambiguous
4.4
Not indicated for use in children and adolescents
Unambiguous
4.4
[...] is recommended for children only for the indication [...]
Ambiguous
For Sect. 5 of the SmPC, the information on study data with pediatric patients was classified according to whether study data for pediatrics were provided for the respective medicinal product, whether it was stated that no studies were conducted with children and adolescents, or whether children and adolescents were not explicitly mentioned in this section.
For further analyses, the medicinal products were categorized according to marketing authorization type, national or centralized. The term centralized marketing authorization was defined as the granted marketing authorization of a medicinal product on the basis of a marketing authorization recommendation by the EMA and a subsequent final marketing authorization granted by the European Commission [21]. A national marketing authorization was defined as a marketing authorization for a medicinal product granted under the national marketing authorization procedure, the decentralized procedure, or the mutual recognition procedure (German Medicinal Products Act, Articles 21 and 25b) [9].
2.4 Measures to Ensure Data Quality
To ensure consistent data quality, we developed a detailed standard operating procedure and tested its comprehensibility through pilot searches. In addition, we created a standardized recording table to be used for the documentation of each SmPC analyzed. Based on these documents, seven pharmacists who performed the analyses of the SmPCs were intensively trained in order to ensure standardization of the search process. In addition, a staggered quality control was implemented: every search carried out was independently checked by other members of the search team. Disputed assessments were decided by consensus by the research team leadership, consisting of four experienced clinical pharmacists. In addition, halfway through the data collection period, 10% of the searches were randomly reviewed by pharmacists who were not involved in the search, and less than 10% of these checks showed discrepancies. After completion of the data collection, another plausibility check of all data collected was carried out.
2.5 Statistics
Descriptive statistics were used to characterize the SmPCs. We used chi-square tests with Yates correction to compare the proportion of indications with unambiguous information by marketing authorization period (years 1996–2006 or 2007–2021) and by type of marketing authorization (national or centralized). We also used chi-square tests with Yates correction to compare the proportion of disclosed contraindications for the entire pediatric population by marketing authorization period. As the option of centralized marketing authorization was established in 1995, and in our dataset the first medicinal product authorized via this procedure was from 1996, 1996 was chosen as the lower limit for the comparison of marketing authorization periods before and after the introduction of the Pediatric Regulation 2007. A p-value ≤ 0.05 was considered to indicate statistical significance.
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3 Results
3.1 Characteristics of the Investigated Medicinal Products and the Corresponding SmPCs
For the 452 pediatric-relevant active substances analyzed, a total of 8575 different medicinal products were listed in the ABDA database, with a median of eight (Q25/Q75: 3/21; min/max: 1/254) medicinal products per active substance (Fig. 1).
Fig. 1
Process for identification and characterization of medicinal products and related Summaries of Product Characteristics (SmPCs)
The active substance with the most medicinal products was pregabalin (3.0% of all medicinal products; 254/8575), followed by oxycodone (2.3%; 200/8575) and quetiapine (2.0%; 169/8575; OSM Table 1).
For 98.7% (8464/8575) of the medicinal products, an SmPC was available in the databases or from the marketing authorization holder. An SmPC was not accessible for 1.3% (111/8575) of the medicinal products. In 93.5% (7911) of the 8464 SmPCs included in the analysis, the last update at the time of the search in the year 2021 was up to 5 years ago (2017–2021), for 6.5% (553/8464) of the SmPCs more than 5 years ago (< 2017).
Of the 8464 medicinal products, 93.4% (7907/8464) had a national marketing authorization and 6.6% (557/8464) had a centralized marketing authorization (OSM Table 2). A total of 30,354 different indications (national marketing authorization: 28,678 indications; centralized marketing authorization: 1676 indications) were identified. This corresponds to a median of three (Q25/Q75: 1/4; min./max.: 1/24) indications per SmPC in the 8464 evaluated SmPCs (Fig. 1).
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3.2 Characterization of the Information Provided in the SmPCs
For 72.4% (21,974/30,354) of the 30,354 identified indications, the SmPCs contained unambiguous information on whether the medicinal product was authorized for use in pediatrics (Table 2).
In 54.6% (12,007/21,974) of these indications, pediatric-specific information, such as age- or weight-related specifications, was available; in 45.4% (9967/21,974) of the indications for which unambiguous information was provided, a contraindication was disclosed for all children and adolescents from birth to 18 years of age. More details on pediatric-specific information provided in SmPCs are presented in OSM Tables 3 and 4.
Table 2
Percentage of unambiguous, ambiguous, and missing indication-related information in (Therapeutic indications, Posology and method of administration, Contraindications, and Special warnings and precautions for use) of the Summary of Product Characteristics examined by type of marketing authorization, based on all 30,354 indications examined
National marketing authorization
Centralized marketing authorization
Total
Unambiguous information
71.6% (20,525/28,678)
86.5% (1449/1676)
72.4% (21,974/30,354)
Ambiguous information
24.8% (7098/28,678)
12.1% (203/1676)
24.1% (7301/30,354)
No pediatric-specific information
3.7% (1055/28,678)
1.4% (24/1676)
3.6%
(1079/30,354)
Ambiguous information was provided for 24.1% (7301/30,354) of the indications, and no pediatric-specific information was provided for 3.6% (1079/30,354) of the indications, resulting in a total of 27.6% (8380/30,354) of indications with ambiguous or missing information on children and adolescents. Those indications concerned 31.4% (2656/8464) of the SmPCs.
The proportion of indications for which unambiguous information was provided in the SmPCs differed between medicinal products with national marketing authorization (71.6%; 20,525/28,678) and medicinal products with centralized marketing authorization (86.5%; 1449/1676; p < 0.001).
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3.3 Changes in the Provided Information Over Time
As shown in Fig. 2, from the marketing authorization year 2007 onwards and thus since the Pediatric Regulation came into force, an increase in the proportion of unambiguous information was observed for both nationally and centrally authorized medicinal products.
Fig. 2
Percentage of Summaries of Product Characteristics (SmPCs) providing unambiguous information in (Therapeutic indications, Posology and method of administration, Contraindications, and Special warnings and precautions for use) by type of marketing authorization
For the marketing authorization period between 1996 and 2006, unambiguous information for pediatric patients was provided for 63.8% (7466/11,694) of the indications. From the authorization year 2007 onwards, after the Pediatric Regulation came into force, a higher proportion of 82.1% (12,349/15,040) of indications with unambiguous information was identified (p < 0.001; Table 3).
Table 3
Percentage of indications for which unambiguous information was provided by type of marketing authorization and authorization period
1996–2006
2007–2021
Chi-square with Yates correction
Total
National marketing authorization
63.3% (7112/11,227)
81.4% (11,254/13,831)
p < 0.001
73.3% (18,366/25,058)
Centralized marketing authorization
75.8% (354/467)
90.6% (1095/1209)
p < 0.001
86.5% (1449/1676)
Total
63.8% (7466/11,694)
82.1% (12,349/15,040)
p < 0.001
100% (19,815/26,734)
To avoid selection bias, the 26,734 indications of medicinal products with marketing authorizations from 1996 onward were examined since the centralized marketing authorization procedure was introduced in 1995 and the first medicinal product authorized via this procedure in our dataset was from 1996
With regard to indications for which unambiguous information was provided, the proportion of disclosed contraindications for all children and adolescents under 18 years of age increased from 34.6% (950/2745) in the authorization period 1997–2001 to 50.7% (1357/2674) in the authorization period 2017–2021 (p < 0.001; Fig. 3).
Fig. 3
Percentages of disclosed contraindications for the entire pediatric population and pediatric-specific information (age- or weight-related specifications) related to indications for which unambiguous information was provided in the Summaries of Product Characteristics
3.4 Data from Clinical Trials in Pediatric Patients
Concerning SmPCs containing at least one indication without unambiguous pediatric-specific information, data from pediatric clinical trials for the respective medicinal product were provided in 39.2% (1042/2656; corresponding to 3576/8380 [42.7%] affected indications) of these SmPCs. In a further 2.0% (53/2656; corresponding to 146/8380 [1.7%] affected indications) of these SmPCs, explicit reference was made to the absence of pediatric clinical trials; and in 58.8% (1561/2656; corresponding to 4658/8380 [55.6%] affected indications) of these SmPCs, clinical trials in pediatric patients were not mentioned.
4 Discussion
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 [11‐14, 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 [34‐36]. 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.
5 Conclusion
In more than a quarter of all indications investigated, Sects. 4.1, 4.2, 4.3, and 4.4 (Therapeutic indications, Posology and method of administration, Contraindications, and Special warnings and precautions for use) contained no or only ambiguous information on the use of the medicinal products in pediatric patients. In almost half of the indications for which unambiguous information was provided, the use of the medicinal product was excluded across the board for all pediatric age groups. In summary, a high information deficit for the pediatric population and a considerable scope for interpretation for readers due to ambiguous information was identified. Although changes can already be perceived since the Pediatric Regulation came into force, measures should be intensified to provide more precise pediatric-specific information for the treatment of children and adolescents in the SmPCs and thus ultimately improve drug safety for pediatric patients.
Acknowledgements
We would like to thank the pharmacists supporting the structured search of the Summary of Product Characteristics.
Declarations
Funding
For this publication, no funding was received.
Conflicts of interest
Astrid Bertsche reports grants from UCB Pharma GmbH and honoraria for speaking engagements from Biogen GmbH, Desitin Arzneimittel GmbH, Eisai GmbH, GW Pharma GmbH, Neuraxpharm GmbH, Shire/Takeda GmbH, UCB Pharma GmbH, and ViroPharma GmbH. The other authors declare they have no conflicts of interest.
Authors' Contributions
Conceptualization: All authors. Investigation: Markus Herzig, Simone Eisenhofer, Meike Ruschkowski. Methodology: Simone Eisenhofer, Meike Ruschkowski, Martina Patrizia Neininger. Data curation: Markus Herzig. Formal analysis: Markus Herzig. Writing—original draft: Markus Herzig, Simone Eisenhofer, Martina Patrizia Neininger. Writing—review and editing: Meike Ruschkowski, Antje Neubert, Astrid Bertsche, Thilo Bertsche. Supervision: Martina Patrizia Neininger.
Ethics Approval
Not applicable.
Informed Consent
Not applicable.
Consent for Publication
Not applicable.
Code Availability (software application or custom code)
Not applicable.
Data Availability
The data that support the findings of this study are available upon reasonable request.
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