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EMEA Herbal Medicinal Products WP
Scientific Assessment of Herbal Medicinal
Products Dr. Konstantin Keller
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Mandate of the HMPWPEMEA Management Board,
December 18, 2001

• Outcome of activities
• Scientific guidelines on quality, safety and
  efficacy

A. CPMP (CVMP / Quality) Guidelines Publication
on the EMEA website in the folder of the relevant
CPMP WP (QWP, SWP, EWP) making reference to the
work done by the HMPWP Examples Guidelines on
Quality and Specifications
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Mandate of the HMPWPEMEA Management Board,
December 18, 2001

• B) Working documents not adopted by CPMP / CVMP

Publication on the EMEA website in a specific
HMPWP folder Note added for clarification The
views presented in this document are those of the
HMPWP, which has been created as a forum for
exchange of experience in the field of herbal
medicinal products. This document is released for
the purpose of transparency and has no legal
force with respect to CD 2001/83 EEC Examples
Guidelines on safety, efficacy, regulatory
questions, core-data on herbal drugs
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Work Programme of the HMPWG2003-2004

• Quality
• Concept Paper for a NfG on biopharmaceutical
  characterisation of herbal medicinal products
• Compilation of general quality questions answered
  by the HMPWP
• Implementation of WHO Good Agricultural and
  Collection Practises

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Work Programme of the HMPWG2003-2004

• Safety
• NfG on non-clinical testing Implementation of
  the final CPMP/SWP NfG
• Position papers related to HMP containing Estrago
  le Methyleugenole a- and ß Asarone Sassafras
  / Safrole Capsaicin Quassin / Quassia
  amara Pulegone / Menthofuran Hypericine /
  Hypericum

Impact of EU Scientific Committee on Food
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Work Programme of the HMPWG2003-2004

• Safety
• Safety of Celandine (Chelidonium
  majus)assessment of hepatotoxicity
• CPMP (1992) list of herbal drugs with serious
  risksupdate / extension

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Work Programme of the HMPWG2003-2004
Regulatory Implementation of the CTD amended
version of Annex 1 of CD 2001/83 EC Level of
evidence of efficacy required for a certain
claim EC Directive on trad. herbal medicinal
products, e.g. possible format of a list of
traditional herbal substances
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Common Technical Document (CTD) Questions and
Answers March 2003
Question 9 Herbal medicinal products After 1
July 2003, do applications for Herbal Medicinal
Products have to follow the EU-CTD-format? Answer
After 1 July 2003 it is also mandatory for
applications for Herbal Medicinal Products to
follow the EU-CTD-format. Further guidance on
requirements for herbal products will be
published in the near future.
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Common Technical Document (CTD) Annex 1 to CD
2001/83 (final rev. 2003)
General Concept Herbal medicinal products differ
from conventional medicinal products. They are
intrinsically associated with the particular
notion of herbal substances and herbal
preparations. Additional specific requirements
dealing with Module 3 must be identified to take
into account their nomenclature, structure, the
characteristics of their manufacturers and the
manufacturing process employed. Modules 1, 2, 4
and 5 are applicable.
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Common Technical Document (CTD) Annex 1 to CD
2001/83 (final rev. 2003)
Presentation and format of the dossier Special
guidance on herbal medicinal products  For the
purposes of this NTA the terms "herbal substances
and herbal preparations" shall be considered
equivalent to the terms "herbal drugs and herbal
drug preparations", as defined in the Eur. Pharm.
For herbal medicinal products applications,
applicants should take into account below
referred to guidance in addition to what is
already explained in the core-Structure of the
Modules 2 and 3.
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Draft concept paper on the implementation of
different levels of scientific evidence in
core-data for herbal drugs May 2003
Minimum requirements for different levels of
evidence related to certain claims acceptable for
indications to be approved in marketing
authorisations referring to Article 10(1)(a)(ii)
of CD 2001/83/EEC (Well-established
use). Explains current approach of the Working
Party in drafting core-data for herbal drugs.
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Levels of EvidenceWell-established use CD
1999/83 EC and Annex 1 to CD 2001/83 EC (final
rev. 2003)
The documentation should cover all aspects of
the safety and/or efficacy assessment and must
include or refer to a review of the relevant
literature, taking into account pre- and
post-marketing studies and published scientific
literature concerning experience in the form of
epidemiological studies and in particular of
comparative epidemiological studies. With
respect to the provisions on well-established
medicinal use it is in particular necessary to
clarify that bibliographic reference to other
sources of evidence (postmarketing studies,
epidemiological studies, etc.) and not just data
related to tests and trials may serve as a valid
proof of safety and efficacy of a product if an
application explains and justifies the use of
these sources of information satisfactorily.
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Draft concept paper on the implementation of
different levels of scientific evidence in
core-data for herbal drugs
A) Major claims High level of evidence (Level
Ia, Ib Grade A)  The claims - For the
treatment, cure or management of any serious
disease or disorder and - For the prevention of
any serious disease or disorder should be
reserved for products with high level of evidence
only .
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Draft concept paper on the implementation of
different levels of scientific evidence in
core-data for herbal drugs

• B) Medium claimsMedium level of evidence (Level
  IIa, IIb, III Grade B)
• The following claims may be acceptable
• Reduction of the risk of a disease / disorder
• Reduction in frequency of a discrete event
• Aids/assists in the management of a named symptom
  / disease / disorder
• Relief of symptoms of a named disease or disorder

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Draft concept paper on the implementation of
different levels of scientific evidence in
core-data for herbal drugs

• C) Minor claimsGeneral evidence (Level IV,
  Grade C) 
• The following claims may be acceptable
• Relief or management of symptoms of a minor,
  self-limiting disease / disorder that does not
  require medical intervention for diagnosis or
  monitoring.
• Description of a pharmacological action related
  to management of symptoms of a minor,
  self-limiting disease / disorder that does not
  require medical intervention for diagnosis or
  monitoring.

If general evidence is submitted, additional
supporting evidence, e.g. pharmacological data,
may be necessary for acceptance.
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Work Programme of the HMPWG2003-2004
Efficacy SOP Recording core-data for herbal
drugs/products Core data on herbal drugs,
assessment of ESCOP/WHO monographs
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Core Data available / in preparation
Stimulant Laxatives core SPC of the (former)
CPMP dated May 1994
Frangula bark (DE) Senna leaf (DE) Alexandrian
Senna pods (DE) Tinnevelly Senna pods (DE)
No update found necessary until now No
experiences with applications for MR
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Core Data available / in preparation
Valerian root (DE)
Published on the EMEA website in September
1998 Consensus achieved (in 1998) 2 successful MR
applications a) Valerian root powder (1998)RMS
UK, CMS AU, GR, I, PORT b) Valerian root
extract (2002)RMS DE CMS AU, IR
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Core Data available / in preparation
Ispaghula husk (DE)

• First release for consultation January 1999
• Second release for consultation delayed from
  April 2000 to July 2002
• Implementation of EMEA MB decision by EMEA in
  autumn 2002
• Consultation from November 2002 to February 2003
• Final document March 2003

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Core Data available / in preparation
Ispaghula husk (DE)

• 4.1 Therapeutic Indications
• Herbal Medicinal Product
• For the treatment of habitual constipation
• As adjuvant in the symptomatic treatment of
  diarrhea
• In conditions in which easy defecation with soft
  stools is desirable, e.g. after rectal or anal
  surgery, anal fissures ..
• In conditions that need an increased daily fiber
  intake e.g. as an adjuvant in IBS, as an adjuvant
  to diet in hypercholesterolemia.

Decision by majority in indications b and d !
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Core Data available / in preparation
Ispaghula husk (DE)
1 successful MR application (1996) RMS DE CMS
AU, BE, GR I PORT UK Indication a)
Laxative 1 successful MR application for a
combination product Ispaghula husk / Guar Gum
(1997) RMS DK CMS AU BE LUX SE Indication
d) hypercholesterolemia
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Core Data available / in preparation
Ispaghula seed (DE)Psyllium seed (DE)final
March 2003
4.1 Therapeutic Indications Herbal Medicinal
Producta) for the treatment of habitual
constipation b) In conditions in which easy
defecation with soft stools is desirable, e.g.
after rectal or anal surgery, anal fissures ..
Consensus achieved under the current criteria of
the HMPWP
No experiences with applications for MR
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Core Data available / in preparation
Calendula flower (AU) final March 2003
4.1 Therapeutic Indications Herbal Medicinal
Product for the symptomatic treatment of minor
inflammations of the skin (such as sunburn) or
the oral mucosa, and as an aid in healing of
minor wounds.
Consensus achieved under the current criteria of
the HMPWP
No experiences with applications for MR
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Core Data available / in preparation
Passion flower (SE, BE from March 2003)Melissa
leaf (SE, BE from March 2003) Hop strobile (SE,
BE from March 2003)

• Consultation from November 2002 to February 2003
• Discussion will continue in July 2003

No experiences with applications for MR
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Core Data available / in preparation
Devils claw root (FR)

• Consultation from November 2002 to February 2003
• Discussion of comments will continue in July 2003

No experiences with applications for MR
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Core Data available / in preparation
St. Johns wort (PT)

• Decision to postpone discussions until safety
  issues are solved (May 1999)
• Decision not to prepare core-data (July 2002)
• Decision to not longer follow the topic in the
  HMPWP and recommendation to decide on safety
  actions on a national basis (February 2003)

No experiences with applications for MR
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Core Data available / in preparation
Peppermint oil (PT)

• Release for consultation agreed in November 2002
• Consultation Period from November 2002 to
  February 2003
• Discussion of comments will take place in July
  2003

Consensus achieved in November 2002 under the
current criteria of the HMPWP
No experiences with applications for MR
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Core Data available / in preparation
Peppermint oil (PT)
  ii) Inhalation Herbal medicinal product for the
relief of symptoms in coughs and colds.  iii)
Cutaneous use Herbal medicinal product for
topical application for the a) relief of coughs
and colds, b) relief of pruritus and pain in
irritable skin conditions, c) symptomatic relief
of mild to moderate tension headache.
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Core Data available / in preparation
Peppermint oil (PT)

• 4.1. Therapeutic indications
•  i) Oral use
• Herbal medicinal product for the
• symptomatic treatment of digestive disorders such
  as flatulence and minor spasms.
• symptomatic treatment of discomfort and of
  abdominal colic and distension experienced by
  patients with irritable bowel syndrome.
• c) symptomatic treatment of coughs and colds.

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Core Data available / in preparation
Peppermint leaf (PT) draft November 2002
4.1. Therapeutic indications Herbal medicinal
product for the symptomatic relief of minor
digestive disorders.
No consensus achieved / decision by majority
No experiences with applications for MR
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Core Data available / in preparation
Nettle leaf (HUN) draft November 2002
4.1. Therapeutic indications Herbal medicinal
product used as adjuvant in the symptomatic
treatment of minor articular pain. (dry extracts
as specified in the core-data)
No consensus achieved / decision by majority
No experiences with applications for MR
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Core Data available / in preparation
Primula root (AU) draft February 2003
4.1. Therapeutic indications Herbal medicinal
product for the relief of symptoms of the upper
respiratory tract in cough and colds with viscous
mucilage
Consensus achieved under the current criteria of
the HMPWP
No experiences with applications for MR
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Core Data available / in preparation
Linseed (DE) draft February 2003
4.1. Therapeutic indications Herbal Medicinal
Producta) for the treatment of habitual
constipation b) In conditions in which easy
defecation with soft stools is desirable, e.g.
after rectal or anal surgery, anal fissures ..c)
as a demulcent preparation for the symptomatic
treatment of gastrointestinal discomfort
Consensus achieved under the current criteria of
the HMPWP
No experiences with applications for MR
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Challenges

• Impact of a future directive on traditional
  herbal medicinal products
• Repetition of discussions related to
• Interpretation of the provisions related to
  well-established use? well-established use
  in the centralized procedure? Herbal
  well-established use?
• Level of evidence required for well-established
  and traditional use?

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Grading of Recommendations
Future minimum for WEU ?Requirements HMP gt
Chemicals?
New products serious diseases major
claimsminor claims
well-established
A
Herbal medicinal product for... (treatment,
prevention ...)
B
C
Traditionally used without supportive scientific
evidence
Traditional medicinal product
T
Fraudulent or misleadingclaims
X
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Challenges
Basis of core-data Ongoing update of monographs
by ESCOP not yet completed Bibliographic data
submitted by ESCOP often not complete to address
all aspects of well-established use Differences
between WHO and ESCOP monographs Limited
experience in some Member States due to the
absence of licensed products Use of documents /
data from national applications?
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Summary
Problems related to the assessment of quality are
almost resolved Implementation of ICH
requirements is a challenge, but solutions can be
found (ICH 6?) Safety and pharmacovigilance
become more important Assessment of efficacy
remains the major challenge Progress has been
made since the EMEA MB created an option of
publication of core-data for information
purposes Members of the HMPWP, including
observers from CADREAC, are engaged in preparing
core-data for herbal drugs
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Summary
After introduction of a draft directive on
traditional HMP the position of some Member
States has become more restrictive Some Member
States find now a positive assessment of HMPs
outside a traditional labelling extremely
difficult or impossible if grade A evidence (at
least one randomized, controlled clinical trial
of good quality) is absent The level of evidence
will be addressed in the pharmacological section
of the core data for future adaptation to the new
CD There is very limited experience in MR for
HMP Improvement of guidelines and criteria
requires practical experience with real
applications.