Toxicological assessment compilation of selected examples of raw materials for homeopathic and anthroposophic medicinal products - Part 2.

The present successor article comprises more than 180 substances representing a continuative compilation of toxicologically evaluated starting materials prompted by the wide use and high number of homeopathic and anthroposophic medicinal products (HMP) on the market together with the broad spectrum of active substances of botanical, mineral, chemical or animal origin contained therein, and by the equally important requirement of applying adequate safety principles as with conventional human medicinal products in line with the European regulatory framework. The February 2019 issue of the Regulatory Toxicology and Pharmacology journal includes the antecedent article bearing the same title and entailing safety evaluations of more than 170 raw materials processed in HMP. This part 2 article highlights scientific evaluation following recognized methods used in toxicology with a view to drug-regulatory authority's assessment principles and practice in the context of HMP, and offers useful systematic, scientifically substantiated and simultaneously pragmatic approaches in differentiated HMP risk assessment. As a unique feature, both articles provide the most extensive publicly available systematic compilation of a considerable number of substances processed in HMP as a transparent resource for applicants, pharmaceutical manufacturers, the scientific community and healthcare authorities to actively support regulatory decision making in practice.

Key elements of legal environments for medical use of cannabis in different countries.

Worldwide, a highly dynamic development of regulatory strategies for cannabis flowers and cannabis-derived products for medical use can be observed. Conditions laid down in the Single Convention on Narcotic Drugs are basic, and implementation in countries is diverse.As early as 1998, the Netherlands was the first Member State of the European Union (EU) to establish a strategy to provide patient access to cannabis for medical use. Since then, more and more Member States of the European Union have facilitated access to cannabis for medical use. A comparable development has taken place outside Europe. This article describes the current situation in the Netherlands and presents selected highlights of developments within and outside Europe to demonstrate the broad spectrum of strategies. Key parameters are identified that should be considered when changing or amending regulatory frameworks on cannabis for medical use. In addition to the establishment of adequate regulatory frameworks, there is a substantial need to generate adequate scientific data.

[Cannabis for medical purposes : Impact of the law of 6 March 2017 on physicians]. / Cannabis als Medizin : Auswirkungen des Gesetzes vom 6. März 2017 auf die Ärzteschaft.

The law on the amendment of the narcotics law and other regulations, which was accepted by consensus by the German Parliament, significantly expanded the options for the use of cannabis-based medicinal products. In individual cases, already approved cannabis-based medicinal products can also be prescribed outside the approved indication at the expense of the statutory health insurance funds (GKV). The cost of treatment with cannabis flowers and extracts as well as dronabinol, which are not approved under the drug law, will also be covered by the GKV upon application. Physicians must advise their patients on the options of treatment with cannabis-based medicinal products and support them in applying for reimbursement. The prescription of unauthorized medical cannabis products poses particular challenges, as there is no summary of product characteristics that is mandatory for authorized finished products. In addition, physicians are obliged to participate in an accompanying survey. To this end, they must send data to the Federal Institute for Drugs and Medical Devices providing information about treatment with cannabis-based medicinal products. When prescribing medical cannabis products as defined in the Act of 6 March 2017 amending the law on narcotic drugs and other regulations, physicians assume a special responsibility that goes far beyond the responsibility for the use of authorized finished medicinal products.

[Cannabis for medical purposes-the law of March 2017 and its history]. / Cannabis zu medizinischen Zwecken ­ Das Gesetz vom März 2017 und seine Vorgeschichte.

Since March 2017, the law amending narcotic and other regulations has expanded the options for prescribing cannabis-derived medicines by doctors. Under certain conditions, patients can be treated with cannabis-derived medicines at the expense of the statutory health insurance. With a prescription, cannabis-derived medicines may be available that are not approved as a finished medicinal product. The reasons for this lie in particular in court decisions from the years 2005 and 2016.The decisive legal regulation increases the responsibility of doctors and pharmacists in supplying their patients with cannabis-derived medicines. A five-year monitoring survey is being conducted by the Federal Institute for Drugs and Medical Devices (BfArM) to evaluate the effects on patient care. In order to ensure the supply of cannabis-derived medicines in the future, the cultivation of cannabis in Germany is planned under the conditions of the 1961 Single Convention on Narcotic Drugs under the control of a cannabis agency.

The potential of three different PCR-related approaches for the authentication of mixtures of herbal substances and finished herbal medicinal products.

BACKGROUND: Herbal substances and preparations thereof play an important role in healthcare systems worldwide. Due to the variety of these products regarding origin, composition and processing procedures, appropriate methodologies for quality assessment need to be considered. A majority of herbal substances is administered as multicomponent mixtures, especially in the field of Traditional Chinese Medicine and ayurvedic medicine, but also in finished medicinal products. Quality assessment of complex mixtures of herbal substances with conventional methods is challenging. Thus, emphasis of the present work was directed on the development of complementary methods to elucidate the composition of mixtures of herbal substances and finished herbal medicinal products. HYPOTHESIS/PURPOSE: An indispensable prerequisite for the safe and effective use of herbal medicines is the unequivocal authentication of the medicinal plants used therein. In this context, we investigated the potential of three different PCR-related methods in the characterization and authentication of herbal substances. METHODS: A multiplex PCR assay and a quantitative PCR (qPCR) assay were established to analyze defined mixtures of the herbal substances Quercus cortex, Juglandis folium, Aristolochiae herba, Matricariae flos and Salviae miltiorrhizae radix et rhizoma and a finished herbal medicinal product. Furthermore, a standard cloning approach using universal primers targeting the ITS region was established in order to allow the investigation of herbal mixtures with unknown content. RESULTS: The cloning approach had some limitations regarding the detection/recovery of the components in defined mixtures of herbal substances, but the complementary use of two sets of universal primer pairs increased the detection of components out of the mixture. While the multiplex PCR did not retrace all components in the defined mixtures of herbal substances, the established qPCR resulted in simultaneous and specific detection of the five target sequences in all defined mixtures. CONCLUSION: These data indicate that for authentication purposes, complementary PCR-related methods are highly recommendable for the analysis of herbal mixtures in parallel.

Herbal medicinal products in pregnancy - which data are available?

This review aims to highlight recent approaches concerning usage of (traditional) herbal medicinal products in pregnancy and to discuss appropriate strategies to handle limited information. Therefore, published monographs of the Committee on Herbal Medicinal products (HMPC) and selected publicly funded webpages, medicinal handbooks, publications and industry and health care organisations webpages were evaluated. While within the monographs of the HMPC a rather conservative approach could be found (mainly because of lacking nonclinical and/or clinical studies), all other sources display a wide variety of information or assessments, thereby often giving contradictory recommendations. However, some experience with the usage of herbal substances/preparations exists in daily clinical practise without clinical trials or observational studies and some herbal substances/preparations are also used as food/food supplements/cosmetics/medical devices. Discussions should be started how to use that knowledge and experience to adjust regulatory decisions on a case-by-case basis, if possible.

Future visions for traditional and herbal medicinal products--a global practice for evaluation and regulation?

Medicinal plants and traditional medicines have been used worldwide since ancient times. Currently, there is neither a globally consented terminology nor a harmonized regulatory approach. Nevertheless, it is common sense that quality, efficacy and safety should be assessed following scientific standards, addressing particulars and considering an adequate level of risk management. A global market for traditional medicines is emerging, if not already existing. Therefore, a constructive communication about regulatory systems for herbal and traditional medicinal products should be enforced. Best practice standards might be developed according to current scientific knowledge in order to improve mutual acceptance of data, sets of monographs and assessments. Overall, a convergence of the diverse regulatory systems might save resources and lead to an adequate availability of herbal and traditional medicinal products to the patients without neglecting public health.

Use of herbal medicinal products among children and adolescents in Germany.

BACKGROUND: Germany is a country with a high use of herbal medicinal products. Population-based data on the use of herbal medicinal products among children are lacking. The aim of this study is to investigate the prevalence, patterns and determinants of herbal medicine use among children and adolescents in Germany. METHODS: As data base served the German Health Interview and Examination Survey for Children and Adolescents (KiGGS), a representative population based survey conducted 2003-2006 by the Robert Koch Institute. 17,450 boys and girls aged 0-17 years provided information on drug use in the preceding seven days. Herbal medicinal products were defined according to the European and German drug laws. SPSS Complex Sample method was used to estimate prevalence rates and factors associated with herbal medicine use. RESULTS: The prevalence rate of herbal medicinal product use amounts to 5.8% (95% confidence interval 5.3-6.3%). Use of herbal medicine declines along with increasing age and shows no difference between boys and girls in younger age groups. Teenage girls are more likely to use herbal medicines than teenage boys. Two thirds of herbal medicines are used for the treatment of coughs and colds; nearly half of herbal medicines are prescribed by medical doctors. Determinants of herbal medicinal product use are younger age, residing in South Germany, having a poor health status, having no immigration background and coming from a higher social class family. Children's and parents-related health behavior is not found to be associated with herbal medicine use after adjusting for social class. CONCLUSIONS: Use of herbal medicinal products among children and adolescents between the ages of 0 and 17 years in Germany is widely spread and shows relatively higher rates compared to international data. This study provides a reference on the use of herbal medicinal products for policy-makers, health professionals and parents. Further studies are needed to investigate the effectiveness and safety of specific herbal medicinal products, potential effects of long term use as well as possible interactions of herbal medicinal products with concomitantly used conventional medicines.

Assessment of genotoxicity of herbal medicinal products: application of the "bracketing and matrixing" concept using the example of Valerianae radix (valerian root).

An assessment of genotoxicity is a precondition for marketing authorization respectively registration of herbal medicinal products (HMPs), as well as for inclusion into the 'Community list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products' established by the European Commission in accordance with Directive 2001/83/EC as amended, and based on proposals from the Committee on Herbal Medicinal Products (HMPC). In the 'Guideline on the assessment of genotoxicity of herbal substances/preparations' (EMEA/HMPC/107079/2007) HMPC has described a stepwise approach for genotoxicity testing, according to which the Ames test is a sufficient base for the assessment of genotoxicity in case of an unequivocally negative result. For reducing efforts for testing of individual herbal substances/preparations, HMPC has also developed the 'guideline on selection of test materials for genotoxicity testing for traditional herbal medicinal products/herbal medicinal products' (EMEA/HMPC/67644/2009) with the aim to allow testing of a standard range of test materials which could be considered representative of the commonly used preparations from a specific herbal drug according to a 'bracketing/matrixing' approach. The purpose of this paper is to provide data on the practical application of this bracketing and matrixing concept using the example of Valerianae radix, with the intention of facilitating its inclusion in the "Community list". Five extraction solvents, representing the extremes of the polarity range and including also mid-range extraction solvents, were used, covering the entire spectrum of phytochemical constituents of Valerianae radix, thereby including polar and non-polar constituents. Extracts were tested in the Ames test according to all relevant guidelines. Results were unequivocally negative for all extracts. A review of the literature showed that this result is in accordance with the available data, thus demonstrating the lack of a genotoxic potential. In conclusion the two guidelines on genotoxicity provide a practically applicable concept. Valerianae radix has no genotoxic potential, supporting its use in HMPs and its inclusion in the Community list.

Regulation of medicinal plants for public health--European community monographs on herbal substances.

The European legislation on medicinal products also addresses the medicinal use of products originating from plants. The objective of the legislation is to ensure the future existence of such products and to consider particular characteristics when assessing quality, efficacy, and safety. Two categories are defined: i) herbal medicinal products can be granted a marketing authorisation; and ii) traditional herbal medicinal products can be granted a registration based on their longstanding use if they are complying with a set of provisions ensuring their safe use. The Committee on Herbal Medicinal Products (HMPC) was established at the European Medicines Agency (EMA) to provide monographs and list entries on herbal substances and preparations thereof. Meanwhile, approx. 100 monographs have been published, which define a current scientific and regulatory standard for efficacy and safety of herbal substances and herbal preparations used in medicinal products. This harmonised European standard will facilitate the availability and adequate use of traditional herbal medicinal products and herbal medicinal products within the European Union. Consequent labelling shall also enable patients and health care professionals to differentiate medicinal products from other product categories like cosmetics, food supplements, and medical devices.

[The regulatory framework for complementary and alternative medicines in Europe]. / Europäische Gesetzgebung zu besonderen Therapierichtungen.

Medicinal products from complementary and alternative medicine are in Germany a regular part of the health care system. Herbal, homeopathic, anthroposophic and traditional medicinal products are highly accepted by the population. The German Medicines Act obliged the competent authorities to consider the particular characteristics of complementary and alternative medicines. The European regulatory framework defined the status of herbal medicinal products, traditional herbal medicinal products and homeopathic medicinal products within the directive 2001/83/EC. The committee for herbal medicinal products (HMPC) was established at the European Medicines Agency in London (EMEA); for homeopathic medicinal products there is a specific working group established by the Heads of Medicines Agencies. Harmonisation of medicinal products from complementary and alternative and traditional medicine in Europe was enforced by implementation of directive 2001/83/EC in national legislations of member states. The provisions of this directive will substantially influence the development of the European market during the forthcoming years.