Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Peculiarities and Challenges of Herbal Medicinal Products -
Assessment of Herbal Medicinal Products within the Regulatory Environments of the European Community and the United States ***

Christine Kriete (Abschlußjahr: 2009)

Language: English

Medicinal plants represented the original source for primary health care in ancient times and are now under consideration as valuable resources for rationalised phytopharmaceuticals intended for the treatment of unspecific disorders as well as ethical diseases. Using natural resources rather than chemically based substances for the development of novel medicinal products has been attributed to the recognition of herbal active compounds unique structural functions as well as phytochemical properties. Furthermore, the polyvalent and multi-target modes of action acknowledged as synergism have contributed to the re-discovery of herbal plants as valuable resources.

Traditionally applied or well-established herbal medicinal products (thmp, hmp) have likewise been converted from former herbal remedies developed on the basis of empirical knowledge and prior human experience into rational phytopharmaceuticals. Particularly, in Germany the system of a Rational Phytotherapy was implemented in classical medicines and the legal status of hmp and thmp was foreseen by the rules laid down in the Germany Drug Law (AMG).

The economical, social and medicinal potential of hmp has attracted industry (AESGP, BHA, EFPIA, etc.), scientific societies (ESCOP, Europam, GA, KoopPhyto, etc.), and academia. National health policies (Swiss BSV, etc.), consumer organisations and health care providers (BEUC, EHPA, etc.) have likewise recognised the benefit of hmp. Within the United States, the intention to legalise botanical products as assessed drugs rather than as dietary supplements has emerged, though to a lesser extent and a certain delay. The foundation of scientific societies and governmentally driven institutions, for example National Centres for Herbal Medicines and Complementary and Alternative Medicines, has been resulted.

Regarding the scientific evaluation and evidence-based research on herbal products, Germany supported the elaboration of harmonised data on commonly used medicinal plants. The Commission E Monograph'-system was reviewed and updated by the European Scientific Cooperative on Phytotherapy (ESCOP) that provided for the basis of Community Monographs and the Community List. Therein, consented scientific knowledge of (traditional) herbal substances and herbal preparations derived from certain plant species are stated. Currently established monographs on herbal substances and preparations derived thereof and legally binding entries into the Community List of traditional herbal substances and preparations contained in thmp are intended to provide for a harmonised basis on which the evaluation and assessment of a proposed (t)hmp should be performed.

With respect to the required pre-clinical and clinical testing, manufacturers must understand that the creation and authorisation of hmp demands an exhausted development programme. The quality of the herbal matters is thereby crucial, since the efficacy and safety of an hmp in future correlates with the pharmaceutical quality. Therefore, an exhausted quality control programme at each development stage is vital. A comprehensive, batch-specific authentication and specification of each the herbal substance, the herbal preparation, and the resulting hmp is required. However, proper performed in process controls allow for a certain reduction of the testing procedures, whereas assurance of an appropriate stability and batch-to-batch consistency represent extra challenges.

Concerning the complex mixture of heterogenous constituents, co-factors, and mediators serving as enhancer or suppressor requires special research techniques and appropriate pre-clinical and clinical development strategies. Examinations of pharmacokinetic items and the bioavailability of the herbal preparation or finished hmp in question offer thereby certain advantages that permit the determination of constituents-efficacy as well as exposure-response relationships. These key parameters built up the basis for the scientific sound confirmation of proposed therapeutic effects, the evaluation of in vitro results in view of the predictable clinical relevance, and the formulation of potent hmp containing refined or enriched herbal preparations. However, these achievements have only been gained for the minority of currently established hmp. Due to the marginal knowledge of the underlying mode of action and the behaviour of both the preparation in its entirety and the individual compounds in the human organism, the estimation of a reasonable dosage regime is in some cases restricted or virtually impossible. In addition, characteristic organoleptic properties may compromise the blinding of the study medication and, moreover, the shortage of (hard) endpoints might prevent the conduction of regulatory required pivotal randomised clinical trials. Hence, properly designed single blind or non-blinded clinical trials and observational studies are considered as a suitable alternative that has meanwhile gained acceptance by some authorities based in the European Community. However, controlled randomised clinical trials are generally necessitated to demonstrate the efficacy and superiority of the hmp in relation to existing therapeutic interventions. Epidemiological study results, post-marketing experiences in humans, and pharmacovigilance data are thereby included in the assessment of the benefit-risk-ratio performed by legislators of the European Community and the United States.

Irrespective of the remaining hurdles and incongruous regulatory issues, the creation and authorisation of hmp within the current legal framework seems to be more successful than in the past. Although herbal products clearly represent borderline products, the movement towards rationalised hmp has emerged and allows for the authorisation as evidenced medicinal products. Consumers, patients, and medicinal professions have begun to consider hmp not only as reliable alternatives to chemically defined medicines, but also as first-line interventions for the treatment of semi-ethical diseases, particularly when vulnerable patient populations are concerned. As such, hmp represent reasonable therapeutic interventions. At best, the pre-clinical and clinical investigation of established and novel hmp should be intensified to ensure that no potential hazard to human health remain uncovered, in particular when infants, children and pregnant as well as women of childbearing potential are concerned.

Pages: 140, Annexes: 3, pages: 3