Operational guidance:

Information needed
to support clinical trials
of herbal products
TDR/GEN/Guidance/05.1
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Design and layout: Lisa Schwarb

Operationnal Guidelines_OK 17.11.2005 15:38 Page 1

Operational guidance:
Information needed
to support clinical trials
of herbal products
Operationnal Guidelines_OK 17.11.2005 15:38 Page 2

| CONTENTS

1. | INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

2. | CHEMISTRY-MANUFACTURING-CONTROL (CMC)
CONSIDERATIONS FOR HERBAL PRODUCTS . . . . . . . . . . . . . . . . 4
2.1. Overview of CMC evidence needed to support
clinical trials for herbal products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.2. Information needed to support a clinical trial
for a herbal product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.3. Information on herbal product proposed
for phase 3 studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

3. | NON-CLINICAL CONSIDERATIONS FOR HERBAL PRODUCTS

3.1. Introduction: Information needed for a conventional drug . . . . . . . . . 7
3.2. Information needed to support a clinical trial
for a herbal product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

4. | CLINICAL CONSIDERATIONS FOR HERBAL PRODUCTS

4.1. Introduction: Information needed for a standard intervention . . . . . . 9
4.2. Information needed to support phase 2 trials . . . . . . . . . . . . . . . . . . . 10
4.3. Information needed to support phase 3 trials . . . . . . . . . . . . . . . . . . . 11

5. | ETHICAL CONSIDERATIONS IN CLINICAL TRIALS

WITH HERBAL PRODUCTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

APPENDIX 1
List of contributors to this document . . . . . . . . . . . . . . . . . . . . . . . . 14

APPENDIX 2
Glossary of key terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

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1. | INTRODUCTION

Herbal and other traditional pharmacologic therapies are in widespread use

throughout the world. Such widespread use suggests, but does not assure,
that traditional medicines have a favourable risk-benefit ratio. Rather, tradi-
tional medicines may be regarded as a rich source of potentially attractive
therapies. The actual benefits and risks remain to be evaluated by clinical
trials supported and conducted according to the principles of modern clini-
cal science.

Justification for a clinical trial of a conventional drug involves four sets of

issues: chemical-manufacturing-control (CMC) issues, non-clinical issues,
clinical issues, and ethical issues. Two unique characteristics of herbal prod-
ucts are that they are multi-component mixtures, and that substantial prior
human use precedes their formal investigation. These features have impor-
tant ramifications for CMC, non-clinical, clinical, and ethical issues.

International organizations and national authorities have published state-

ments for supporting clinical trials of herbal products, in which the justifica-
tion required for conventional drugs has been adapted to the particular case
of traditional medicines.

These statements tend to be broad in their coverage, very detailed, and often
out of date. In addition, national statements focus on the regulatory require-
ments and languages of individual countries. There is a need for an interna-
tional organization such as WHO-TDR to issue clear and concise recommen-
dations for the data needed to support clinical trials in which herbal prod-
ucts are evaluated for diagnosis or treatment of diseases.

The target audience for these recommendations is primarily the community

of clinical investigators wishing to evaluate the benefits and risks of herbal
products. The secondary audience is national regulatory authorities. The fol-
lowing recommendations are written in broad terms so as to be useful for
clinical investigators as well as to be compatible with the global regulatory
climate. It is hoped that these recommendations will lead to well supported
clinical trials of traditional herbal products, approvable by national regulato-
ry authorities, and thus lead to improved chances of determining which
herbal products are effective and safe for clinical diseases.

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2. | CHEMISTRY-MANUFACTURING-CONTROL
(CMC) CONSIDERATIONS FOR HERBAL
PRODUCTS

For conventional, chemically-defined drug products, general considerations

are synthesis and/or purification of the active pharmaceutical ingredient
(API), manufacturing of the product that is administered to the patient, and
control of these processes so that the API and product are made repro-
ducibly. Since herbal products are manufactured from plant material, these
considerations have to be translated into terms appropriate to this plant
source.

2.1. | Overview of CMC evidence needed to support clinical

trials for herbal products
2.1.1. Unlike standard chemically-defined drugs, herbal products have often
had substantial human use prior to clinical trial evaluation. To capitalize on
the use of this information in protocols to evaluate these products, it is
important that the chemistry, manufacturing, and control of the product to
be used mimics that for the traditionally-used formulation.
2.1.2. Also unlike conventional drugs, herbal products are mixtures of at
least partially uncharacterized constituents. It is postulated that being a
mixture provides a therapeutic advantage, in that unknown constituents
may combine in an additive or synergistic fashion with known con-
stituents to provide more efficacy than would be provided by the known
constituent alone. Thus, evaluation of herbal products does not require
attempts to purify the medicines down to known or otherwise single
chemical constituents.
2.1.3. For herbal products, “analysis of the active pharmaceutical ingredi-
ent(s)” may be best approached by analysis of one or more hypothesized
active ingredient(s), analysis of a chemical constituent that constitutes a
sizable percentage of the total ingredients, and a chemical fingerprint of
the total ingredients. The latter two analyses are surrogates for analysis
of the unknown constituents that contribute to efficacy.
2.1.4. Specifications for acceptable values of analytic data should reflect
the best available standards. For herbal products, variation of content
from batch to batch may be an issue, and several analytical procedures
may be needed to adequately quantify their constituents.

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2.1.5. Because herbal products are sourced from plants, levels of contami-
nating herbicides and pesticides as well as toxic contaminations must
particularly be addressed. The presence of adulterants should also be
considered.
2.1.6. Many herbal medicines are in fact polyherbal. Plants may either be
mixed before extraction or the extracts may be combined. In either case,
information on each individual plant species used must be collected.
2.1.7. Herbal products intended for administration to humans are clinical
trial materials, and they should therefore be made following the princi-
ples of GMP. Indeed, in many countries, the facilities have to have a cur-
rent certificate of GMP.

2.2. | Information needed to support a clinical trial for a herbal

product
2.2.1. Information on the herbal product proposed for phase 1/2 studies
Phase 1/2 trials are performed on few subjects under tight medical super-
vision. While details on specification and quality control of the product used
for the trial are required, GMP standards for CMC processes may, in general,
not be required at this stage.

HERBAL SUBSTANCE:
• description of the plant: genus, species (cultivar where appropriate);
region(s) and country(ies) of origin; time of harvest; parts to be harvested
• plant processing: drying, mechanical disruption, solvent extraction (aque-
ous or organic solvents, others)
• analytical procedures
• specification
• storage conditions/shelf life.

HERBAL PRODUCT:
• amount of active ingredient
• list of excipients
• type of product (tablet, capsule, etc.) and its method of manufacture
• analysis of putative active ingredient(s) via chemical or biological parameters
• analysis of a sizeable chemical constituent (analytical marker compound)
• analysis via chemical fingerprint (analytical markers)
• analysis for lack of contamination by pesticides, herbicides, heavy metals,
synthetic drug adulterants, microbials, toxins, etc.

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• dissolution studies
• storage conditions and stability over the length of the trial
• specification against which a certificate of analysis can be assessed before
the clinical trial material is released.

2.3. | Information on the herbal product proposed for phase 3

studies
Phase 3 trials are performed on large number of patients and are often car-
ried out prior to registration and general use. Therefore, GMP standards are
needed prior to phase 3 trials. In practice, this means performing generally
the same procedures as for phase 1/2 trials, but more extensively and with
more stringent oversight.

HERBAL SUBSTANCE:
• as above for phase 1/2 trials.
In addition:
• statement that the plant is cultivated according to Good Agricultural
Practices or harvested according to Good Wildcrafting Practices
• reference batch.

HERBAL PRODUCT:
• as above for phase 1/2 trials.
In addition:
• environmental impact statement.

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3. | NON-CLINICAL CONSIDERATIONS FOR

HERBAL PRODUCTS

3.1. | Introduction: Information needed for a conventional drug

Non-clinical information generally needed to support a clinical investigation
of a conventional drug consists of data on efficacy, toxicity, and pharmacoki-
netics.

Efficacy is demonstrated in enzyme/receptor assays, in vitro, and in

animal models.

Toxicity is investigated:
• in vitro and in mice to assess genotoxicity
• in vitro to assess cytotoxicity
• in rodents to assess single-dose acute toxicity and maximum tolerated dose
• in one rodent model and one non-rodent model to investigate repeat dose
(1, 3, 6, 9 months) toxicological effects
• in a rodent model and in the rabbit to assess reproductive toxicity
• in the rat to assess carcinogenicity.

Pharmacokinetic analyses relate to:

• absorption of the drug from the gut after e.g. oral dosing, or
mobilization from the injection site after injection
• distribution of the API around the body
• rate of drug metabolism, the metabolic enzyme involved, and
the nature of the metabolites produced.

3.2. | Information needed to support a clinical trial for

a herbal product
3.2.1. Efficacy
It is recommended that the appropriate literature sources be searched for all
available evidence on efficacy. Examples of such sources are medical and sci-
entific journals, pharmacopeia, and articles on traditional medicines. Only if
there are obvious gaps in the information or the total amount of data is
insubstantial should it be necessary to perform new efficacy experiments.

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3.2.2. Toxicology
It is imperative that the appropriate literature sources (as above) be reviewed
for the toxicities of the herbal products in prior human experiences or exist-
ing animal data. The need for additional non-clinical studies prior to clinical
trials depends on the following considerations:
• similarities between the new and old preparations, in terms of product
characteristics, and usages in clinical settings.
• scale and exposure (dosage/duration) of the proposed new clinical studies.
• frequency and severity of any known toxicity.

Thus, in general, requirements for non-clinical studies may range from none
for early phase, small, studies using the same preparations that have been
used extensively and without known safety problems, to a complete set of
conventional toxicology studies for relatively new products in large phase 3
trials. For many herbal products, certain non-clinical studies may be neces-
sary but can be conducted concurrently with the proposed clinical trials.

3.2.3. Pharmacokinetics
It is technically difficult to work in this area as often the APIs are unknown
and there are likely to be a large number present. Also, the dosing regimen
needed for the clinical studies can be deduced from traditional methodology,
rather than deduced from animal pharmacokinetics. Therefore non-clinical
pharmacokinetics is not absolutely required.

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4. | CLINICAL CONSIDERATIONS FOR

HERBAL PRODUCTS

Good Clinical Practice should be applied in all stages of clinical trials to

ensure that quality and ethical requirements for clinical studies are met. It is
expected that a traditional practitioner familiar with the product proposed
for investigation be an integral member of the protocol development team,
where those traditional practitioners exist. For all clinical trials, biostatisti-
cians should be consulted to ensure that the sample size is sufficient to satis-
fy the primary endpoint/objective.

4.1. | Introduction: Information needed for a standard intervention

Phase 1 studies are designed to determine safety associated with increasing
doses in normal volunteers, as a precursor to phase 2 and phase 3 trials. In
addition, phase 1 studies investigate toxicity and drug levels in states in
which drug levels might be altered: the fed vs. the fasted state, in renal or
hepatic impairment. Mechanisms of action are also investigated in phase 1.

Phase 2 studies evaluate the efficacy of a range of dosages in individuals

with disease. Phase 2 studies typically start by evaluating the maximum tol-
erated dose determined in the prior phase 1 normal-volunteer studies. If this
dose is effective, dose-ranging downwards would be investigated. If the
phase 1 dose is ineffective, it is possible that higher doses will demonstrate
efficacy and only mild intolerance, so dose-ranging upwards may be per-
formed. Phase 2 dose-ranging studies utilize a relatively small number of
patients per dosage group. Placebo and standard intervention groups may be
included. If surrogate markers rather than disease endpoints are used in the
phase 2 studies, it may be necessary to repeat dose-ranging in phase 3 trials
with more valid disease endpoints.

Phase 3 studies are expanded trials of safety and efficacy. They are performed
after preliminary evidence suggesting efficacy for the intervention has been
obtained, and are intended to gather the additional information about efficacy
and safety that is needed to evaluate the overall benefit-risk ratio of the inter-
vention and to provide an adequate basis for general clinical use. Phase 3 stud-
ies usually include large numbers (several hundred to several thousand) of
subjects, may involve human populations with broader entrance characteris-
tics than were used in the phase 2 trials, and involve statistical comparison of
the intervention to standard and/or placebo interventions.

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4.1.1. Important note on phase 1, phase 2, and phase 3 trials

Phase 1 studies in normal volunteers are generally unnecessary for herbal tra-
ditional medicines. The substantial prior human use of traditional dose regi-
mens of herbal medicines generally conveys reasonable confidence that these
regimens can safely be administered to small numbers of carefully monitored
clinical subjects in phase 2 trials.

Care should be taken that phase 3 trials are not undertaken prematurely, but
are instituted only after dose-ranging phase 2 data are available. The purpose
of a clinical trial is to evaluate an intervention for a clinical condition.
Positive (or negative) data can lead to a recommendation to use (or not to
use) the treatment. Use of a suboptimal dose that is safe but ineffective does
not serve the needs of the community. Although the trial indicates only if the
particular tested dose of the intervention was ineffective, the community may
conclude that all doses of the intervention are ineffective, and patients will be
denied possible benefits from the intervention. The inappropriate rejection of
an intervention, “because phase 2 studies did not preceed a phase 3 trial, and
a suboptimal dose was used in the phase 3 trial”, is common for herbal medi-
cines.

For some herbal products, there may exist previous research that has deter-
mined the optimum dose for a treatment. For others, dose-ranging phase 2
studies will need to be performed prior to beginning more extensive phase 3
studies. Therefore, if the scientific literature does not contain scientifically
valid dose-ranging data, the investigator should first perform phase 2 trials
to generate these data.

For dose-ranging studies, clinical investigators should consult biostatisticians

for examples of dose-ranging schemes, and decide which scheme best fits the
needs of the particular clinical problem.

4.2. | Information needed to support phase 2 trials

Although data from prior human experience may suggest confidence in the
clinical safety of the product, it is important to verify tolerance in phase 2
trial patients. Both the literature review and the provisions in the protocol to
be performed should focus on complete review of the clinical safety parame-
ters. Examples of safety parameters are:

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Organ system Safety parameter

Neurological: lack of neurologic symptoms
Skin: clinical evidence of lack
of allergic reactions
Musculoskeletel: lack of arthritis or myalgias, normal values
of CPK
Gastrointestinal: clinical evidence of tolerability
Liver: normal values of SGOT or SGPT, alkaline
phosphatase, total bilirubin,
Kidney: normal values of BUN or creatinine
Endocrine system normal values of albumin or total protein, uric
and metabolism: acid, glucose, cholesterol, amylase or lipase,
sodium/potassium, calcium
Cardiovascular: normal EKG and blood pressure
Haematopoietic: normal values of complete blood count
Additionally: more intensive investigation of any organ
system likely to be particularly effected by
the product

4.3. | Information needed to support phase 3 trials

• Safety data as in 4.2. If the population has broader entrance characteristics
compared to the populations of prior trials, the favourable safety profile
shown for constricted populations in prior trials may or may not convey
to the broader populations in the phase 3 trials. Arguments that the prod-
uct is likely to be safe in the broader population should be stated, and the
phase 3 protocol should include re-testing of the safety parameters.
Another reason to re-test safety parameters in phase 3 trials is the greater
chance of identifying rare adverse events with the large number of
patients used in phase 3.
• Preliminary efficacy data from phase 2 trials.
• Evidence from dose-ranging trials that the chosen dosing regimen is likely
to be the optimum regimen with respect to safety and efficacy.

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5. | ETHICAL CONSIDERATIONS IN CLINICAL

TRIALS WITH HERBAL PRODUCTS

All of the fundamental ethical principles of human participation in research

apply equally to herbal remedies and research involving these compounds.
Consent must be obtained, subject selection must be equitable, risks and
benefits must be weighed and must be favourable to the potential partici-
pant, and experimental design must be sound.

Concerns that particularly apply to clinical trials with herbal products

include:
- Product adulteration (has it been documented?)
- Interactions between herbal remedies and other entities (rarely under-
stood)
- Reproductive and organ toxicity data (may be minimal)
- Prior dose finding (likely to be incomplete).

The uncertainty in these areas must be clearly disclosed to all concerned,

particularly during the informed consent process.

In many regions of the world, strong belief that herbal medicines will be
beneficial and safe may introduce bias, which can be minimized by careful
attention to study design including appropriate control groups.
Where possible, the community from whom the medicine originates should
be consulted during the course of the research, and the results and benefits
of the research should be shared with this community.

As in other types of research, a well trained, ethical investigator is the best

assurance of patient safety in research. Therefore, skilled clinicians should be
chosen as investigators to assure prompt recognition and appropriate treat-
ment of any observed adverse event or worsening of a pre-existing condition.

Ethics committees must apply the same vigilant attitude towards herbal
studies as they do towards conventional treatment protocols.

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APPENDIX 1 | LIST OF CONTRIBUTORS

TO THIS DOCUMENT

Dr Jonathan Berman (Chair), Director, Office of Clinical and

Regulatory Affairs, National Center for Complementary and
Alternative Medicine, 6707 Democracy Blvd, Suite 401, Bethesda
MD 20892, USA. Tel: +1 301 594 7105; Fax: +1 301 480 3621;
E-mail: bermanjo@mail.nih.gov

Dr Francis Crawley (Principal Rapporteur), European Forum for

Good Clinical Practice, Schoolbergenstraat 47, B-3010 Kessel-Lo,
Belgium. Tel: + 31 16 3503 69; Fax: + 31 16 350 369;
E-mail: fpc@pandora.be

Dr Vasantha Muthuswamy (Associate Rapporteur), Senior Deputy

Director General & Chief, Division of Basic Medical Sciences,
Indian Council of Medical Research, Post Box 4911, Ansari
Nagar, New Delhi 110 029, India. Telefax: +91 11 26589791(O),
23092868(R); E-mail: muthuswamyv@icmr.delhi.nic.in or
vasanthamuthuswamy@yahoo.co.uk

Dr Angela Bowen, President, Western Institutional Review Board

(WIRB), 3535 Seventh Avenue, SW, Olympia, Washington
985002, USA. Tel: +1 360 252 2440; Fax: +1 360 252 2490;
E-mail: abowen@wirb.com

Dr Shaw Chen, Associate Director for Special Product Review -

Botanical Drug and Medical Officer,
DHHS/FDA/CDER/OND/ODEV, CRP2 Room 103, Rockville
MD 20850, USA. Tel: +1 301 827 2601; Fax: +1 301 827 2317;
E-mail: shaw.chen@fda.hhs.gov

Dr Vichai Chokevivat, Director General, Department for

Development of Thai Traditional and Alternative Medicine,
Ministry of Public Health, Tiwanond Road, Nonthaburi 11000,
Thailand. Tel: +662 590 2603-4; Fax: +662. 590-2605;
E-mail: vichai@health.moph.go.th

Prof Win Gutteridge, Consultant and Visiting Professor, LSHTM,

10 Soleoaks Drive, Sevenoaks, Kent, U.K. Tel: +44 1 732 454 923;
E-mail: win.gutteridge@btopenworld.com

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Dr Zhang Lei, Associate Professor and Head, Clinical Evaluation

Group, Division of Traditional Medicine, Center for Drug
Evaluation, State Food and Drug Administration,
Jia-1 Fuxing Road, Beijing 100038, People’s Republic of China.
Tel: +8610-68585566-455; Mobile: 13911331089;
E-mail: zhanglei37@sina.com

Ms Gugu Mahlangu, Director, Medicines Control Authority

of Zimbabwe, P.O. Box UA 559, Union Avenue, Harare,
Zimbabwe. Tel: 263 4 736981/5; Mobile 263 91 303 178;
Fax: 263 4 736 980; E-mail: mcaz@africaonline.co.zw

Dr Jenny Mueller, Head, Clinical Research/Drug Safety Affairs,

German Pharmaceutical Industry Association, Robert-Koch-
Platz 4, 10115 Berlin, Germany. Tel: +49 30 279 09-1 14;
Fax: +49 30 279 09- 3 14; E-mail: jmueller@bpi.de

WHO/TDR SECRETARIAT
Dr Juntra Karbwang, Clinical Coordinator, Special Programme for
Research and Training in Tropical Diseases (TDR), World Health
Organization, Geneva, Switzerland.Tel: +41 22 791 3867;
Fax: +41 22 791 4774; E-mail: karbwangj@who.int

Dr Vladimir Lepakhin, Assistant Director-General, Health

Technology and Pharmaceuticals, World Health Organization,
Geneva, Switzerland. Tel: +41 22 791 4417/4804/4035;
E-mail: lepakhinv@who.int

Dr Robert Ridley, Director, Special Programme for Research and

Training in Tropical Diseases (TDR), World Health Organization,
Geneva, Switzerland. Tel: +41 22 791 3803/3906;
E-mail: ridleyr@who.int

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APPENDIX 2 | GLOSSARY OF KEY TERMS

Herbal substance:
Material derived from the plant(s) by extraction, mechanical
manipulation, or some other process.

Herbal product:
The herbal material administered to clinical subjects.

Herbal product synonyms:

Herbal remedy, herbal medicine, herbal drug, botanical drug.

Active pharmaceutical ingredient (API):

The chemical constituent that accounts for the efficacy
or other therapeutic effect of the herbal substance or herbal product.

Chemistry-manufacturing-control (CMC):
The chemical and manufacturing processes, and the control
of these processes, that are used to create the herbal substance and
the herbal product.

Good Manufacturing Practices (GMP):

A set of standards that ensures that CMC procedures are
performed as well as possible.

Good Clinical Practices (GCP):

A set of standards that ensures that clinical procedures
are performed as well as possible.

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Comments and suggestions on all aspects of this Operational Guidance

are welcome for consideration in future revisions.
Please correspond with:

Dr Juntra Karbwang
Clinical Coordinator
Special Programme for Research and Training
in Tropical Diseases (TDR)
World Health Organization
CH-1211 Geneva 27
Switzerland

Tel: +41 22 791-3867 (8)

Fax: +41 22 791-4774
E-mail: karbwangj@who.int
Website: www.who.int/tdr
Mailing address:
TDR
World Health Organization
20, Avenue Appia
1211 Geneva 27
Switzerland

Street address:
TDR
Centre Casai
53, Avenue Louis-Casai
1216 Geneva
Switzerland

Tel: (+41) 22-791-3725

Fax: (+41) 22-791-4854
E-mail: tdr@who.int
Web: www.who.int/tdr