Rationalizing the Use of (Traditional) Herbal Medicinal Products in Children: Current
Situation and New Approaches
Prof. Dr. Andreas Hensel (University of Münster, Germany) provided an overview on
the current use of traditional (T)HMPs in children, discussing both existing practices
and potential new approaches. The World Health Organization emphasizes that “children are no small adults” regarding medicinal treatments, underpinning the ECʼs pediatric regulation initiative
from 2007 aimed at developing child-specific drugs. After 17 years, progress remains
moderate due to limitations in pediatric clinical trials [1], [2].
HMPs have been used since ancient times for minor, self-limiting diseases and are
still widely used in Europe, including pediatric care. Despite general safety, detailed
data on HMP use in children is scarce, especially with respect to dosing studies and
effectiveness studies. Although HMPs are an integral part of pediatric treatment,
drug registration often relies only on adult data, leading to “off-label” use in children. However, children differ from adults in body/organ size, drug metabolism,
absorption, and body composition, necessitating tailored dosing.
Review and extraction of existing data could be a solution but possesses limited regulatory
utility. High-quality controlled clinical studies (RCTs) have ethical and practical
limitations and are very costly. Extrapolation from adult data is standard for many
drugs but untested for plant-derived drugs. In contrast, RWD means using observational
data from various sources, e.g., electronic health records, but requires validation
for regulatory acceptance.
In the past years, the FDA and the EMA began to consider RWD for drug utilization.
Also, the EMAʼs HMPC has included RWD in its 2023 work plan for pediatric HMPs, with
the support of the Pediatric Committee of the EMA. Main challenges for using RWD for
HMPs for children are the collection of continuous and large-scale data and the validation
of the data quality to meet scientific and regulatory requirements [1], [2]. Therefore, there is a need for a concerted action to improve pediatric phytotherapy
by leveraging RWD and addressing the unique challenges in dosing for children.
Herbal medicinal products in daily pediatric practice
Pediatrician Univ.-Doz. Mag. pharm. Dr. med. Ulrike Kastner (Austria) discussed the
frequent use of HMPs in pediatric practice, emphasizing the challenges and off-label
use due to a lack of authorized products for children, especially infants and toddlers.
In pediatric practice, a significant portion of children, around 60%, present with
common cold symptoms and feverish illnesses, mostly viral infections affecting children
under 6 years old. HMPs play a crucial role in this setting, with 85% of children
in Germany receiving at least one HMP annually, and approximately 95% of Austrian
pediatricians prescribing HMPs daily.
The primary indications for HMPs include respiratory tract infections, gastrointestinal
disorders, skin diseases, and psychovegetative disorders. Commonly used medicinal
plants include ivy, primrose, marshmallow, thyme, echinacea, chamomile, peppermint,
and valerian.
HMPs offer several advantages in pediatric treatment. They provide mild treatment
for frequent mild diseases and are, in general, well tolerated by children of all
ages. HMPs are available in various forms like syrups, teas, tablets, and ointments.
These treatments are highly accepted by patients and parents, with some countries
even offering reimbursement through statutory health insurances. The safety of HMPs
is documented through extensive empirical use and routine pharmacovigilance systems.
For respiratory diseases, HMPs exhibit a multimodal mode of action, which includes
secretomotoric, secretolytic, anti-congestive, antitussive, antimicrobial, antispasmodic,
and anti-inflammatory effects, making them effective in treating and preventing infections
and supporting recovery.
Despite these advantages, the use of HMPs in children often occurs outside official
marketing authorizations, leading to “off-label” use, especially in children under 6 years. This practice is due to the complexity
of extrapolating adult data to children, limited data on pediatric use, and the risk
of adverse effects falling on prescribing physicians or parents.
Challenges in integrating HMPs into pediatric practice include the lack of Good Clinical
Practice documentation, the need for time-consuming and resource-intensive database
generation, and a reliance on personal knowledge and interest in medicinal plants.
Future recommendations emphasize the need for official endorsements of HMPs for children
based on RCT, RWD, or extrapolated adult data. Without this, pediatricians will continue
to prescribe off-label, face inadequate dosage recommendations, and encounter more
unverified food supplements or medical devices, risking the loss of an essential treatment
option for children.
In conclusion, there is a critical need for proper data collection, validation, and
official recognition of HMPs to ensure their safe and effective use in pediatric practice.
Real-world data on herbal medicinal products in children – industry food for thought
Angela Müller (European Self-Care Industry Association, AESGP, Germany) explored the
industryʼs perspective on using RWD to improve the evaluation and safe use of HMPs
in children. She emphasized the need for a reflection paper on data requirements for
herbal substances used in children and a research project to ensure the safe use of
herbals in this age group. The HMPC pilot project includes a study protocol and report
focusing on the use of herbals in children, utilizing prescription data from Germany
and Belgium. It aims to create a blueprint for similar studies and emphasizes the
need for representative pediatric data [3].
Collecting RWD on herbals is difficult, noting that many databases do not contain
relevant data on herbal products and that data related to herbal preparations in databases
and scientific publications are often lacking a complete description of the herbal
preparation [4]. Furthermore, a request by AESGP to the 20 data partners of the DARWIN revealed
that only two of them included data on HMPs. Therefore, there is a need for high-quality
RWD publications in scientific literature and for a standardized description of herbal
substances and preparations in publications and databases. Tackling this, AESGP recently
published a white paper to propose clear and consistent descriptions of herbal preparations
in publications and databases to better incorporate HMPs in the future [4].
As a further example of collecting RWD, Angela Müller presented a pharmacy-based RWE
study approach, highlighting the recruitment and engagement process for pharmacists
and consumers. The study aims to generate RWE on the usage and patient-reported outcomes
for an herbal product based on Pelargonii radix.
Overall, Angela Müller underscored the important role of RWD in documenting the use
of HMPs, particularly in children, and advocates for strategic actions to improve
the regulatory framework, data collection, and application of RWE for HMPs. Furthermore,
Müller calls to grant access to the EMA databases to the industry.
Unmet need for real-world studies on the effectiveness of herbal medicinal products
in children
Prof. Dr. Karel Kostev (IQVIA, Germany) highlighted the urgent need for more RWD to
understand the effectiveness of HMPs in pediatric care. There is a growing acceptance
of RWE among regulators, physicians, and patients, noting that clinical trials, particularly
for children, are lengthy and costly [1], [2]. RWD and other studies based on them have gained importance in evaluating the safety
and effectiveness of HMPs. However, despite the increased acceptance of RWE, pharmaceutical
companies are still hesitant to invest in such studies.
Exemplarily, Prof. Kostev presented the prescription patterns of antibiotics and phytopharmaceuticals
for children with respiratory tract infections between 2013 and 2022. Respiratory
infections are common among children and have a high economic impact. Although these
infections are frequently viral, antibiotics are still commonly prescribed, despite
their limited effectiveness in shortening symptom duration and the risk of antibiotic
resistance. The study indicated that antibiotic prescriptions have decreased over
time, while in parallel, the use of HMPs has increased, particularly between 2013
and 2018. This trend suggests a growing awareness among pediatricians on the limitations
and risks of antibiotics [5].
Despite the promising trends, the presentation pointed out the lack of scientific
literature on the efficacy and tolerance of HMPs in children. More RWD and RWE studies
are urgently needed to fill this gap.
Prof. Kostev emphasized the potential of RWE studies, which are significantly cheaper
than clinical trials, to provide valuable insights into the effectiveness of HMPs
and calls for more comprehensive studies and better data access to fully realize the
benefits of HMPs in pediatric care. He highlighted the strengths of the IQVIA Disease
Analyzer database, which contains extensive patient data regarding prescribed and
reimbursed medicines, making it a valuable resource for conducting epidemiological
studies and supporting regulatory decisions.
Capturing use of herbal medicinal products in patient registries and electronic medical
records
Dr. Simone Breitkopf (German Society for Pharmaceutical Medicine, DGPharMed, Germany)
discussed methods for capturing the use of HMPs through patient registries and electronic
medical records, and how these data sources can support research. The presentation
provided an in-depth exploration of the methods and significance of integrating HMP
data into healthcare databases, emphasizing the potential for enhancing regulatory
decision-making through linked RWD as part of the EHDS.
A patient registry, as per the EMAʼs Patient Registry Initiative, is defined as an
organized system that uses observational methods to collect uniform data on a population
defined by a particular disease, condition, or exposure, followed over time. The primary
objective is to leverage existing registries and establish high-quality new ones to
provide an adequate source of post-authorization data for regulatory purposes, such
as pharmacovigilance.
Dr. Breitkopf discussed the different types of registries, including disease registries,
population registries, and product registries. Disease registries focus on specific
diagnoses or conditions, population registries cover comprehensive data across entire
populations (common in Nordic countries), and product registries collect data on patients
exposed to specific medicinal products. Each type of registry collects RWD outside
of RCTs.
Registry-based studies, which utilize the infrastructure and patient populations of
one or more registries to investigate research questions, were highlighted as essential
for analyzing RWD. These studies can be either clinical trials or NISs, as defined
in EU regulation 536/2014. The presentation emphasized the suitability of RWD for
regulatory purposes, citing examples where NISs using RWD supported regulatory assessments.
DARWIN EU, an EMA initiative within the EHDS, already includes the first projects
to make use of routinely collected health data. DARWIN EU collaborates with various
sources, including hospitals, registries, and insurance claims, to access comprehensive
patient data. This initiative aims to link disease registries with nationwide healthcare
administrative databases to enhance the breadth and depth of health data available
for research and regulatory purposes.
Dr. Breitkopf also addressed the inclusion of HMPs in electronic medical records and
patient registries. She suggested using the Pharmacy Product Number (PPN) or the German
pharmaceutical registration number (PZN) to unambiguously identify HMPs in data sources
collecting health data routinely. This would enable the tracking of HMP prescriptions,
dosages, and usage durations, facilitating more detailed analyses and regulatory evaluations.
Dr. Breitkopf emphasized that combining patient information from healthcare, administrative,
and clinical databases could broaden research perspectives and enhance the suitability
of data for regulatory purposes and highlighted the role of integrating HMP data into
patient registries and electronic medical records, underscoring the value of linked
RWD in supporting regulatory decisions and improving patient care outcomes.
Real-world Data and Real-world Evidence to Understand Herbal Medicinal Products in
Children
Dr. Tamar Lasky (Senior Advisor on RWE at the FDAʼs Office of Digital Transformation
[retired], USA) provided the information on U. S. accomplishments on using RWD and
RWE to enhance the understanding of phytopharmaceuticals in pediatric populations
and emphasized the potential of RWD and RWE in regulatory decision-making and drug
development.
The FDAʼs RWE program, initiated in response to the 21st Century Cures Act of 2016,
aims to accelerate medical product development. The FDA created a framework in 2018
for evaluating the use of RWE to support the approval of new drug indications and
post-approval study requirements. RWD, as defined by the FDA, includes data related
to patient health status and healthcare delivery collected from various sources, such
as electronic health records (EHRs), medical claims, registries, and patient-generated
data. RWE is the clinical evidence derived from the analysis of RWD, providing insights
into the usage and potential benefits or risks of medical products [6].
The FDA has several guidances and resources relevant to RWD and RWE, highlight the
increasing importance of these data sources in regulatory decisions. Dr. Lasky noted
that while RCTs remain the gold standard, observational studies based on RWD are crucial
for understanding real-world outcomes and supporting regulatory assessments.
She provided examples of FDA approvals that incorporated RWE, citing a systematic
review of publicly available FDA approval documents from January 2019 to June 2021.
The review found that RWE played a significant role in 88 approvals, with 65 of these
studies influencing the FDAʼs final decisions and 38 being referenced in product labels.
This trend underscores the growing acceptance and utility of RWE in regulatory contexts.
Dr. Lasky also discussed the role of the FDA offices responsible for pediatric drugs,
including the Office of Pediatric Therapeutics, the Division of Pediatrics and Maternal
Health, and the Clinical Pharmacology Pediatrics Program. These offices ensure that
children have access to safe and effective medical products, emphasizing the importance
of pediatric-specific research and regulatory oversight.
The presentation highlighted the FDAʼs approach to botanical drug products, which
includes phytopharmaceuticals. Botanical drugs are intended for diagnosing, curing,
mitigating, treating, or preventing diseases in humans and consist of vegetable materials
such as plant substances, algae, and fungi. The FDA has specific guidance for botanical
drug development, requiring substantial evidence of effectiveness, safety, and adequate
manufacturing controls.
Dr. Lasky suggested potential steps for advancing the understanding of HMPs in children,
such as conducting literature searches, identifying relevant databases (e.g., DARWIN),
and defining variables of interest, including safety and effectiveness outcomes. She
cited examples of studies utilizing RWD, such as the PhytoVIS study [7], which investigated the use of herbal medicinal products in the pediatric population
in Germany.
In conclusion, Dr. Lasky emphasized the great potential of using RWD and RWE to understand
the impact of botanical drugs on pediatric health. This area intersects several unique
fields, including RWD/RWE, pediatric drug development, and botanical drugs, presenting
both challenges and opportunities for future research and regulatory advancements.
Real-world data in the authorization of herbal medicinal products for use in children
– the perspective of the German Federal Institute for Drugs and Medical Devices
Dr. Jacqueline Wiesner (German Federal Institute for Drugs and Medical Devices, [BfArM],
Germany) presented on the role of RWD in the authorization of HMPs for use in children,
providing insights from the perspective of the BfArM.
The EMA has been incorporating RWD into all phases of drug regulation, particularly
for post-marketing surveillance, safety studies, drug utilization, and disease epidemiology.
Therefore, primary care databases are extensively used [8], [9].
Most studies using RWD are descriptive, focusing on incidence or prevalence rates
of clinical outcomes or adverse events, though some comparative analyses also exist.
Sometimes RWD studies generate different outcomes. A further problem is that RWD are
sometimes heterogeneous, and subject to various biases and measurement errors. Therefore,
RWD shall only complement clinical data, but cannot generate clinical evidence by
itself. Additionally, RWD should always be product specific. Data on botanical groups
or on HMPs with different extracts are not useful for registration of an individual
HMP. Despite these challenges, RWD can provide valuable insights, particularly when
combined from multiple databases, such as those available through the DARWIN EU project
[8].
The monographs of the HMPC provide detailed information on the use of various herbal
substances and preparations, including those applicable to pediatric populations.
However, some indications and herbal preparations are not recommended for children
due to safety concerns or lack of sufficient evidence. Out of the well-established
use (WEU) monographs, 8 out of 19 indications (42%) can be used in children below
the age of 12.
Dr. Wiesner provided examples of how RWD can be used to answer specific safety and
usage questions for HMPs in children. These questions include usage patterns in different
age groups, comedications, duration of use, and appropriateness for self-medication.
Dr. Wiesner emphasized the usefulness of RWD in the development of new HMPs and supporting
authorized HMPs and stressed the importance of study design tailored to specific questions
and specific herbal products or preparations. Despite the potential of RWD to enhance
the understanding and regulation of HMPs in pediatric populations, she acknowledged
its limitations, such as data quality, availability, and interpretation challenges
and pointed out the need for careful study design.
Prior to starting RWD investigations, discussions with registration authorities should
be considered to pinpoint the specific questions to be answered and for optimized
design of the study. Dr. Wiesner pointed out that it is essential not to insert to
many questions into one RWD study, as this could lead to reduced impact.
Real-world data: What we want to know, need to know, can know and what is nice to
know
Dr. Emiel Van Galen (Chair of the HMPC, Netherlands) outlined the different dimensions
of RWD, focusing on its potential and limitations in the context of HMPs and discussed
the utilization of RWD related to the use of HMPs in children. He focused on the potential
and current experiences with RWD, emphasizing what is necessary, possible, and beneficial
to know from the perspective of the HMPC.
Dr. Van Galen outlined the relevance of RWD for the HMPC, particularly in establishing
EU herbal monographs and list entries. RWD can support the documentation of therapeutic
use and safe conditions for well-established and traditional herbal substances and
preparations. It can also aid in drafting an EU list of herbal substances.
He discussed the first experiences of the HMPC in 2024 with two pilot Darwin RWD studies.
These studies, although not yet complete, are part of an ongoing learning process
for the committee.
It is important to have a clear and unequivocal research question when searching for
RWD. For example, data on the use of an HMP in different age groups, particularly
focusing on children, should be stratified by age categories such as < 3 years, 3 – 5
years, 6 – 11 years, 12 – 17 years, and adults/elderly. Furthermore, it needs a precise
description of the herbal substance or preparation as an active substance. This clarity
is crucial to avoid irrelevant or missing data, ensuring the output is relevant and
accurate. The description should be detailed enough to capture all necessary information
but not so restrictive that it excludes significant data.
In the pilot searches, RWD can be obtained for periods up to 10 years, but includes
data mostly on prescription medicines. However, the ideal scenario would be to have
comprehensive data on the medicinal use of herbal products by patients and consumers,
incorporating the over-the-counter use of nonprescription medicines as well.
RWD searches by DARWIN are quickly advancing, focusing on stratification of indications
and large databases. HMPC is interested in RWD in the long-term and broad medicinal
use of HMPs, especially in specific age groups. A tailored research question is needed
as well as a clear description of the herbal preparation for successful data retrieval.
In summary, RWD has the potential to enhance the understanding and regulation of HMPs,
particularly for pediatric use. There are significant opportunities of RWD for improving
the evidence base and regulatory framework for HMPs.
