Licensing of Herbal Medicines from Asia in Germany

Transcription

1 Licensing of Herbal Medicines from Asia in Germany Challenges and Experiences TradReg 2017 Regulation of Herbal and Traditional Medicinal Products Challenges of Globalisation International Symposium Bonn, Germany, September 2017 Dr. Markus Veit

2 Examples presented 1. Product according to HMPC monograph (THMP or well-established use) in a national or multinational procedure - e.g. Ginseng product 2. Clinical development project with a full dossier in a national procedure (Germany) Product with modified ginseng extract BST THMP with significant tradition outside the EU Kampo product 4. Extract developed in Asia and registered as first herbal medicinal product with a full dossier via DCP/MRP in most EU member states Veregen 2

3 1. Product according to HMPC monograph Logistics and compliance Transport of materials Import - export of materials - necessary documents, holding times, packaging material Herbal substance (herbal drug): according to GACP availability and import to Germany/EU GMP standards of manufacturing sites Stability of the product in the planned packaging material 3

4 1. Product according to HMPC monograph Quality issues Testing of herbal substance (= herbal drug) and herbal product - regulatory compliance of analytical results in the EU, establishment of testing laboratory Herbal substance (herbal drug): testing according to Ph. Eur. monograph! Test for heavy metals, aflatoxins, pesticides, pyrrolizidine alkaloids according to EU standards Dosage form testing according to Ph. Eur. monograph! 4

5 1. Product according to HMPC monograph Further issues Assessment of potential genotoxicity of herbal substances/preparations ) Readability test Compilation of CTD and marketing authorisation application in Asia or Germany/EU? PV system QP/QPPV Procedure to be chosen (national DCP MRP combination) 5

6 2. Modified ginseng extract BST204 Goal of BST204 project : Development of Global Botanical Drug from Panax ginseng for the treatment of cancer cachexia (or cancer fatigue) 6

7 2. Modified ginseng extract BST204 - Quality BST204 (PRODUCT) is Panax ginseng dry purified extract, which does not contain the genuine extract but an extract preparation that is modified by enzymatic fermentation The extract used is characterised regarding a broad spectrum of relevant components Manufactured under GACP GMP in Europe 7

8 2. Modified ginseng extract BST204 Non-clinic I Primary pharmacodynamics (mouse model) PRODUCT alone comparative effectivity of PRODUCT vs. original extract comparative effectivity of PRODUCT vs. positive control comparative effectivity of PRODUCT vs. active markers Secondary pharmacodynamics 8

9 2. Modified ginseng extract BST204 Non-clinic II Safety pharmacology effect on herg tail current (HEK293 cells) effect on cardiovascular system (incl. potential for QT interval prolongation) in telemetered conscious dogs effect on respiratory functions in conscious rats effect on CNS / neuropharmacological screening in rats Pharmacokinetics (absorption and resulting exposure) dose-exposure relationship (rat) single vs. multiple dosing (rat) vehicle effects (rat) formulation effects (Beagle dog) 9

10 10 2. Modified ginseng extract BST204 Non-clinic III Pharmacokinetic drug interactions CYPs inhibition (human liver microsomes) CYPs induction (human hepatocytes) UGTs inhibition (human liver microsomes) Toxicology Repeated dose (each in SD rats and Beagle dogs): 14-day dose range finding 4-week study followed by a 14-day recovery period 13-week study followed by a 28-day recovery period Genotoxicity Bacterial reverse mutation assay Chromosome aberration test Micronucleus test

11 2. Modified ginseng extract BST204 Clinic I Korea: Randomized, open-label, single-dose, three-sequence, three-period cross-over study : investigation of pharmacokinetics and safety of BST204 (PRODUCT) in healthy male volunteers A study of BST204 for the evaluation of improvement of cachexia and quality of life in gastrointestinal (GI) cancer patients, a singlearm, open, single-center trial : investigator-initiated trial (IIT) 11

12 2. Modified ginseng extract BST204 Clinic II Europe (Germany): Phase I study: "First-in-man study investigating safety, tolerability, and pharmacokinetics of BST204 (PRODUCT) after single and multiple ascending doses and the effect of food in healthy male volunteers Randomized, double-blind, placebo-controlled design for the single and multiple ascending dose part and a randomized, open-label, 2-period, 2 sequence cross-over design for the effect of food Planned: Phase IIa study (therapeutic exploratory), Multicenter, randomized, double-blind, placebo-controlled, 4-arm design with two stages, exploring the effect of BST204 on cancer-related cachexia 12

13 2. Modified ginseng extract BST204 Issues to be solved so far Establishment of extract preparation and scale-up Characterisation of the enzyme used Characterisation and profiling of the extract Establishment of control strategy and appropriate specifications 13

14 3. Kampo product Basics on Kampo medicine Kampo medicine is the Japanese version of East Asian herbal therapy. It was adopted from China approx years ago, but has independently developed in Japan. Already since the 17th century self-medication with powdered Kampo drug products has been wide-spread in Japan. Therapy does not focus on a single plant but on a well composed defined traditional formula, following the concept that the perfect combination of herbs leads to synergistic and manifold effects as well as a higher tolerability of the Kampo product. Today 80 % of Japanese physicians prescribe Kampo herbal medicinal products. 148 formulae have been registered as ethical products and are covered by the national health insurance. At the same time, self-medication is also well established. Distinct extract products have been registered as OTC products since As licensed drugs they are subject to the same quality standards as ethical drugs and are implemented in the Japanese pharmacovigilance system. 14

15 3. Kampo product Basics on Kampo product "Rikkunshito Rikkugast" Ominedo Pharmaceutical Industry Co Ltd Extract obtained from 8 herbal drugs Film-coated tablets Well-established product in Japan (ethical & OTC) THMP application submitted in Germany with the indication "used traditionally for relief of mild gastrointestinal complaints such as loss of appetite, nausea of short duration, epigastric fullness and bloating" Proof of tradition as required by EU and national requirements is based on prescriptions of Kampo physicians in Europe and traditional use in Japan as well as further supportive data Safety based on pharmacovigilance and clinical data from Japan and AMES-Tests together with bibliographic data for the single herbal drugs used in the extract 15

16 3. Kampo product Ongoing registration procedure Two scientific advice meetings with BfArM Additional written scientific advice with BfArM Dossier submitted 11/2015 Two subsequent Assessment Reports received (6-2016, response: , response ongoing) Remaining issues ongoing to be resolved (AMES test & safety data & quality) 16

17 3. Kampo product Main challenges Main issues which have been resolved Testing strategy and specifications for quality control (herbal drugs & extract) Testing strategy for genotoxicity testing and other safety issues Proof of tradition and plausibility of efficacy in the EU 17

18 4. Veregen History 18 Veregen is a prescription product based on an extract from green tea leaves for the treatment of external genital and perianal warts In 1999 Medigene AG in-licensed the global rights for Polyphenon E from Epitome Pharmaceuticals (Canada), original inventors are Mitsui Norin Company, Japan and the Chinese Cancer Institute From Medigene conducted the full formulation, pre-clinical and clinical development program In October 2006 Veregen received US FDA approval as the first botanical drug! Today, Veregen is on the market in more than 20 countries. Approval in most EU member states via DCP & MR Repeat Use Procedure (Germany RMS 2 waves) Trade names: Veregen, Veregreen, Catephen 2 concentrations: 15% (USA); 10% (all other countries)

19 4. Veregen Declaration US Veregen (sinecatechins) Ointment, 15 % is a botanical drug product for topical use. The drug substance in Veregen is sinecatechins, which is a partially purified fraction of the water extract of green tea leaves from Camellia sinensis (L.) O Kuntze, and is a mixture of catechins and other green tea components. Catechins constitute 85 to 95 % (by weight) of the total drug substance which includes more than 55 % of Epigallocatechin gallate (EGCg), other catechin derivatives such as Epicatechin (EC), Epigallocatechin (EGC), Epicatechin gallate (ECg), and some additional minor catechin derivatives, e.g. Gallocatechin gallate (GCg), Gallocatechin (GC), Catechin gallate (Cg), and Catechin (C). In addition to the known catechin components, it also contains gallic acid, caffeine, and theobromine, which together constitute about 2.5 % of the drug substance. 19

20 4. Veregen Declaration EU The herbal drug preparation Polyphenon E is a refined quantified dry extract from the herbal substance Camellia sinensis (L.) O. Kuntze, containing mainly catechins. The total catechin content of Polyphenon E is %; the main catechin component and active marker is (-)- Epigallocatechin gallate (EGCg), which constitutes % of the extract. 20

21 4. Veregen Non-clinical data, safety and pharmacology Safety pharmacology Toxicokinetics Local tolerance Embryo-fetal development or teratogenicity Impairment of fertility Genotoxicity & mutagenicity Carcinogenicity Full set of pharmacological data needed for topical products Pharmacokinetics systemic exposure (EGCg as marker) 21

22 4. Veregen Clinical data Type of study Study design and type of control No. subjects Study treatment Efficacy and safety Phase III Randomized, double-blind, 3-arm, parallel group, placebo-controlled, multicentre 502 Veregen 15% ointment Veregen 10% ointment Placebo ointment Efficacy and safety Phase III Efficacy and safety Phase II/III Pharmacokinetic Phase I Randomized, double-blind, 3-arm, parallel group, placebo-controlled, multicentre Randomized, double-blind, 3-arm, parallel group, placebo-controlled, multicentre Veregen 15% ointment Veregen 10% ointment Placebo ointment Veregen 15% ointment Veregen 10% cream Placebo ointment Placebo cream Open-label, single center 31 Veregen 15% ointment Pharmacokinetic Phase I Pharmacokinetic Phase I Open-label, single center 40 Open-label, multicentre 38 Veregen 15% ointment Veregen 15% ointment 22

23 4. Veregen Main challenges and experiences GMP GACP Concept Testing strategy & setting of specifications Evaluation of clinical data obtained with different specifications Establishment of systemic exposure Divergent questions from EU member states Regulatory classification of post-approval change in DER (line extension) Botanical nature of the product has been no hurdle for reimbursement 23

24 Licensing of herbal medicines from Asia in Germany - Summary YES you can! All types of products (THMP WEU full dossier) could be approved and marketed in EU countries Different procedures different projects! EU regulatory experience is a success factor Seek scientific advice with competent authorities in EU member states 24

25 Contact Dr. Markus Veit i.dras GmbH Fraunhoferstr Planegg / Martinsried Phone: Fax: markus.veit@i-dras.com Web: 25