Safety of Herbal Preparations Herbal Medicinal Products

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Safety of Herbal Preparations/ Herbal Medicinal
Products

• Olavi Pelkonen
• Department of Pharmacology and Toxicology
• University of Oulu, Finland
• Co-opted member of HMPC, EMEA

The Toxicology Forum 2005 Annual European
Meeting, Brussels, Nov 8-10, 2005
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HMPC (Committee for Herbal Medicinal Products)

• First Meeting on September 23, 2004
• Chair elected Konstantin Keller (Germany)
• Vice chair elected Heribert Pittner (Austria)
• Meetings at EMEA 6 per year for 2 to 3 days
• 25 delegates and 25 alternates
• (1 per each EU Member State)
• Members from Norway and Iceland (with separate
  counting of votes)
• up to 5 additional co-opted members

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Goals of Regulation of Herbal Medicinal Products
in the European Union

• Harmonisation of requirements on quality, safety
  and efficacy for herbal medicinal products
• Improvement of pharmacovigilance for herbal
  medicinal products
• Facilitation of free movement of safe herbal
  medicinal products within the European Union

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HMPC Drafting Groups

• Organisatory Matters (Chair E van Galen)
• Quality (Chair D Dempsey)
• Safety and Efficacy (Chair H Pittner)

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(No Transcript)
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Pharmacovigilance/Safety

• EMEA/HMPC/138139/05 Public Statement on the
  allergenic potency of herbal medicinal products
  containing soya or peanut protein (Released for
  consultation April 2005)EMEA/HMPC/138379/05
  Public Statement on Capsicum / capsaicin
  containing herbal medicinal products (Released
  for consultation April 2005)EMEA/HMPC/138309/05
  Public Statement on Chamomilla containing herbal
  medicinal products (Released for consultation
  April 2005)EMEA/HMPC/138381/05 Public Statement
  on the risks associated with the use of herbal
  products containing Aristolochia species
  (Released for consultation April
  2005)EMEA/HMPC/137212/05 Public Statement on the
  use of herbal medicinal products containing
  estragole (Released for consultation April
  2005)EMEA/HMPC/138363/05 Public Statement on the
  use of herbal medicinal products containing
  methyleugenol (Released for consultation April
  2005)EMEA/HMPC/138386/05 Public Statement on the
  use of herbal medicinal products containing
  pulegone and menthofuran(Released for
  consultation April 2005)EMEA/HMPC/139215/05
  Public Statement on the use of herbal medicinal
  products containing asarone (Released for
  consultation April 2005)

http//www.emea.eu.int/htms/human/hmpc/hmpcguide.h
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HMPC Drafting Group Safety Efficacy Agenda

• Draft guideline on non-clinical documentation for
  well-established and traditional herbal medicinal
  products (ongoing)
• Draft guideline on assessment of clinical safety
  and efficacy for well-established and traditional
  herbal medicinal products (ongoing)
• Draft guideline on clinical assessment of fixed
  combinations of herbal substances / herbal
  preparations (published for commenting)
• Monographs and lists (5 2 published for
  commenting)

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Community herbal monographs

• Definition
• Document the purpose of which is
• to provide a scientific summary of all data
  available on the safety and efficacy of a herbal
  substance / herbal preparation intended for
  medicinal use and
• to facilitate a harmonisation of marketing
  authorisations / registrations throughout the EU

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Community herbal monograph

• According to SPC
• Name of the medicinal product
• Qualitative and quantitative composition
• Pharmaceutical form
• Clinical particulars
• 5. Pharmacological particulars
• (For traditional herbal medicinal products
  information on pharmacological properties is not
  required unless such data are available and
  relevant for the safe use of the products)
• 6. Date of compilation

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Community herbal monographSources

• ESCOP Monographs (European Scientific Cooperative
  on Phytotherapy)
• WHO Monographs
• European Pharmacopoeia
• Other Pharmacopoeias
• Any Published Literature
• other information available to national competent
  authorities. e.g. pharmacovigilance data, studies
  etc.

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Community herbal monographsWhich
substance/product first?

• Based on core-data created by the former
  EMEA/CPMP Working Party on Herbal Medicinal
  Products (HMPWP 1997 2004)
• Proposals from AESGP (Association of the European
  Self-Medication Industry) and other organisations
• Final Decision by HMPC

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Community herbal monographs

•  Valerian
•   Linseed
•   Ispaghula husk
•   Ispaghula seed
•   Psyllium seed
•   Senna leaf
•   Senna pods

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Alternative/complementary (drug-like) treatment
options

• Herbal medicinal products (well established vs
  traditional)
• Traditional preparations (European, Chinese,
  Ayurvedic etc)
• Outside the responsibility of the HMPC
• Nutraceuticals
• Nutrients/food supplements
• Homeopathic/anthroposophic products

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Safety concerns of old substances

• Old substances are widely used, but there are few
  formal toxicological studies
• Very little incentives to make such studies no
  protection of data and intellectual property
• Animal experiments are difficult to justify, if
  only the "completeness of dossier is the goal
• What is the value of past experience

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Possible solutions to safety concerns of old
substances

• Require formal studies (as pharmaceuticals
  check-box approach)
• Accept common experience / pharmacovigilance data
  for safety assessment if no serious concerns
• Mixed approach depending on a substance/
  preparation and specific toxicity
• Cause for concern toxicological threshold of
  concern (TTC)

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Problem issues in safety assessment of old
substances

• Certain forms of toxicity not easily recognisable
  in daily use
• Genotoxicity/mutagenicity
• Carcinogenicity
• Reproductive toxicity
• Numerous potential interactions with
  pharmaceuticals

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Mutagenicity/Genotoxicity
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Mutagenicity/Genotoxicity

• The "full set" of ICH/OECD genotoxicity tests
  versus a reduced set of selected tests?
• What is the absolute minimum for acceptance of a
  registration/marketing authorisation of old
  herbal substances
• In current practice, no agency is asking for a
  full genotoxicity testing programme

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Carcinogenicity

• In vivo carcinogenicity tests (24-month rat
  study, 18-month mouse study)
• TG or KO strains (short-term tests)
• Colony forming assays (transformation assays)
• Gap junction inhibition assays

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Safety of herbal products - status

• Boundaries between foods, herbals and
  pharmaceuticals
• Long experience vs formal toxicity studies
• Well-established vs traditional
• Cause for concern (vigilance signals)
• Hidden hazards
• Hazard assessment vs risk assessment