Particular challenges of evaluation of herbal combination products

Transcription

1 Particular challenges of evaluation of herbal combination products Reinhard Länger, PhD, Assoc. Prof. Austrian Medicines and Medical Devices Agency (AGES MEA/BASG) Dept. for Herbal, Homeopathic & Veterinary Medicinal Products Bonn,

2 Disclaimer The views I present do not necessarily represent the views of the AGES Medizinmarktaufsicht / BASG in Austria nor of the (committees of the) European Medicines Agency. R. Länger

3 EU: Herbal combinations are important Traditional European Medicine used primarily herbal combinations Example Central Europe Collection of traditional knowledge and practice in herbal medicine University of Vienna, Dept. of Pharmacognosy More than 400 plant species in traditional use App formulas for combinations reported by informants Only few plants species primarily used in mono-preparations E.g., Arnica montana

4 EU: Herbal combinations important Traditional European Medicine used primarily herbal combinations Old editions of national pharmacopoeias of many member states contain monographs on tea combinations Austrian Pharmacopoeia 1960 Hungarian Pharmacopoeia 1970

5 EU: change of requirements for medicines Mono-products: result of increasing demands Legal requirement for marketing authorisation of medicinal products from app. the middle of the 20th century Continuous increase of the demands regarding documentation of quality, safety and efficacy over the time Data from clinical trials became mandatory Justification of the superiority of the combination compared to the single ingredients Trend for a development of Mono-products supported by evidence of clinical efficacy E.g. Hypericum, Valeriana Only few combinations remained as authorised medicinal products with sufficient evidence of clinical efficacy Traditional combination medicinal products under pressure

6 EU: change of requirements for medicines Dir. 2004/24: new chance for combinations Change of legislation in 2004: New category of Traditional Herbal Medicinal Products (THMP) Medicinal products (also combinations) with long history of medicinal use (> 30 years) and sufficient safety may stay on the market No need for evidence of clinical efficacy Longstanding medicinal use makes efficacy plausible Simplified registration process No change for the requirements for marketing authorisations Evidence of clinical efficacy

7 EU regulatory framework open for combinations Directive 2001/83 as amended Definitions: Medicinal products: any substance or combination of substances presented as having properties for treating or preventing disease Herbal medicinal product: any medicinal product, exclusively containing as active ingredients one or more herbal substances or one or more herbal preparations, or one or more such herbal substances in combination with one or more such herbal preparations. Particular provisions regarding traditional herbal medicinal products Art 16c(1)(a)(iv) Evidence of traditional medicinal use Product itself or a corresponding product in medicinal use >30 years Corresponding product: same active ingredients, the same or similar intended purpose, equivalent strength and posology and the same or similar route of administration Combination must be safe

8 HMPC: development of guidance for combinations Certain flexibility for quality documentation acceptable Primary goal for any medicinal product: Proof of identity of any active ingredient in the finished medicinal product Proof of quantity of any active ingredient in the finished medicinal product Simple for combination of synthetic drugs (Unresolvable) challenge for herbal combination products Approach: Applicant has to try to identify and quantify all active ingredients in the finished product If demonstrably not possible: Joint assays (e.g. flavonoids from all sources) Identification and/or assay as in-process control.. GUIDELINE ON QUALITY OF COMBINATION HERBAL MEDICINAL PRODUCTS / TRADITIONAL HERBAL MEDICINAL PRODUCTS Doc. Ref. EMEA/HMPC/CHMP/CVMP/214869/2006

9 HMPC: development of guidance for combinations Decision trees for identification and assay Identification Assay

10 HMPC: development of guidance for combinations Decision trees for identification and assay Identification Assay

11 HMPC: development of guidance for combinations Decision trees for identification and assay Identification Assay

12 HMPC: development of guidance for combinations Decision trees for identification and assay Identification Assay

13 HMPC: development of guidance for combinations Clinical documentation: Differences! Authorised herbal medicinal products Documentation of an improvement of the benefit/risk ratio or a simplification of therapy. The efficacy and the clinical safety of the fixed combination must be evident from clinical trials or from bibliographic data submitted by the applicant. The indications claimed for a fixed-combination product must be such that the presence of each active substance makes a contribution to the claimed effect. Traditional herbal medicinal products The traditional use of the product or of a corresponding product has to be substantiated. Justification of the plausibility of efficacy GUIDELINE ON THE CLINICAL ASSESSMENT OF FIXED COMBINATIONS OF HERBAL SUBSTANCES / HERBAL PREPARATIONS Doc. Ref. EMEA/HMPC/166326/2005

14 HMPC: EU herbal monographs on combinations EU monographs facilitate authorisation / registration procedures Value of EU herbal monographs: Harmonised approach regarding acceptance of evidence of clinical efficacy, evidence of traditional use, safety THMPs: only in case of a published monograph right for the applicant to use multi-state registration procedures Only 2 combination monographs for long time Valerianae radix + Lupuli flos Thymi herba + Primulae radix

15 EU monograph Valerianae radix + Lupuli flos

16 HMPC: EU monographs on combinations EU monographs facilitate procedures Problem for monographs on fixed combinations Time-consuming development Huge number of potential candidates for such combination monographs New approach with a flexible monograph EU herbal monograph on diuretic tea combinations Assessment of single formulas, references, products Combination of the results in a matrix Applicant may choose out of the possible combinations Limitations regarding number of active ingredients to a maximum of 4 The product information contains relevant sentences from the EU Mono -monographs depending on the active ingredients Next flexible monographs on tea combinations in other indications under development

17 17

18 EU monograph combinations: flexible wording

19 EU: The system works Current status: ~40% of THMPs are combinations Number of granted registrations of Traditional Herbal Medicinal Products in the EU (Source: EMA)

20 EU: The system works Current status: only 18% of authorised HMPs are combinations Number of granted marketing authorisations of herbal medicinal products (HMP) in the EU (Source: EMA)

21 EU: The system works Usually 2-3 active ingredients in combination products Traditional Use Registrations Well-Established Use Marketing Authorisations 21

22 EU: harmonised basis, challenges remain The devil might be in the details Challenges quality documentation Analytics: What is possible in theory? vs. What is reasonable in daily practice? Guideline:. all analytical methods usually applied for identification and assay should be investigated first, e.g. the methods described in the Ph. Eur. General Chapter 2 Methods of analysis. Ph. Eur. Chapter 2: 271 monographs, app. 25 applicable It is up to the applicant to convince the agency that not all active ingredients can be identified or quantified Particularly in the case of traditional multi-ingredient products extremely difficult to find suitable analytical marker compounds in such concentrations that allow a validated identification / quantification.

23 Analytics of combination products Successful examples for identification Herbal drug Mixture of herbal drugs Mixture of herbal drugs Mixture without x Herbal drug x

24 EU: harmonised basis, challenges remain The devil might be in the details Challenges clinical documentation Superiority of the combination in clinical trials At least 4-arm clinical studies necessary For 2 active ingredients: Placebo, active #1, active #2, combination = 4-arm study For 3 active ingredients: Placebo, active #1, active #2, active #3, actives #1+#2, actives #1+#3, actives #2+#3, complete combination = 8-arm study Expensive Actually no authorised herbal combination medicinal product with a new combination in the last decade

25 EU: harmonised basis, challenges remain The devil might be in the details Evidence of traditional medicinal use No problems for existing medicinal products with tradition >30 years But: Combinations originating from other traditions? TCM, Kampo medicine, How to provide evidence of medicinal use? Scientifically meaningful combinations with European plants, but lack of a corresponding product?

26 Traditional European phytotherapy = Therapy with combinations European framework open to combinations Challenges for applicants remain! Länger, BAH Bonn

27 Univ.-Doz. Dr. Reinhard Länger Head of Dept. for Herbal, Homeopathic and Veterinary Medicinal Products BASG - Austrian Federal Office for Safety in Health Care Traisengasse Vienna reinhard.laenger@ages.at