Clinical Evidence for Phytomedicine
The Society for Integrative Phytomedicine (SIPM) is an international organization dedicated to the development of standards for phytomedicine, medicinal fungi, and related natural health products. The work of preparing SIPM Standards is carried out through technical committees composed of experts from academia, industry, regulatory bodies, and healthcare practice.
The procedures used to develop this document and those intended for its further maintenance are described in the SIPM Directives, Part 1. In particular, the different approval criteria needed for the different types of SIPM documents should be noted. This document was drafted in accordance with the editorial rules of the SIPM Directives, Part 2.
SIPM draws attention to the possibility that the implementation of this document may involve the use of intellectual property. SIPM takes no position concerning the evidence, validity or applicability of any claimed intellectual property rights in respect thereof. As of the date of publication of this document, SIPM had not received notice of any patents which may be required to implement this document. However, implementers are cautioned that this may not represent the latest information.
Any trade name used in this document is information given for the convenience of users and does not constitute an endorsement.
For an explanation of the voluntary nature of standards, the meaning of SIPM specific terms and expressions related to conformity assessment, as well as information about SIPM’s adherence to the World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see https://sipm.org/about.
This document was prepared by Technical Committee TC 5, Clinical Evidence.
This is the first edition of SIPM 0400.
A list of all parts in the SIPM 0400 series can be found on the SIPM website.
Any feedback or questions on this document should be directed to the SIPM Secretariat at standards@sipm.org.
1. Introduction
The establishment of clinical evidence is fundamental to the responsible use of phytomedicine in healthcare. While traditional use provides valuable historical context, modern evidence-based practice requires rigorous clinical research to establish safety and efficacy.
This document provides a framework for the generation, evaluation, and reporting of clinical evidence for phytomedicine products. It recognizes the unique challenges of clinical research in phytomedicine, including:
Complexity of multi-component botanical preparations
Variability in product composition between studies
Integration of traditional knowledge with modern research methods
Ethical considerations in studying traditional remedies
The standard addresses the complete evidence generation process:
Classification of evidence types and their relative weight
Study design considerations specific to phytomedicine
Quality assessment of clinical studies
Transparent reporting of methods and results
This document is intended to support:
Researchers designing clinical studies of phytomedicines
Regulatory bodies evaluating marketing authorization applications
Healthcare professionals assessing evidence for clinical practice
Manufacturers developing evidence-based products
2. Scope
This document specifies requirements for the generation, evaluation, and reporting of clinical evidence for phytomedicine products.
It is applicable to:
Clinical trials and observational studies of phytomedicines
Evidence synthesis and systematic reviews
Assessment of traditional use evidence
Regulatory submissions and health claims substantiation
This document covers:
Herbal medicinal products
Medicinal fungi products
Traditional herbal preparations
This document does not cover:
Preclinical (in vitro and animal) studies
Specific disease conditions or products
Regulatory requirements for specific jurisdictions
Normative references
The following documents are referred to in the text in such a way that some or all of their content constitutes requirements of this document. For dated references, only the edition cited applies. For undated references, the latest edition of the referenced document (including any amendments) applies.
[[[CONSORT,CONSORT 2010 Statement: Updated Guidelines for Reporting Parallel Group Randomized Trials]]]
[[[GRADE,Grading of Recommendations Assessment, Development and Evaluation (GRADE) Handbook]]]
[[[WHOTM,WHO General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine]]]
[[[DECLHELSINKI,Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects]]]
3. Terms and definitions
For the purposes of this document, the following terms and definitions apply. Terms defined in SIPM-0001 also apply where relevant.
3.1. clinical evidence
information derived from clinical research that contributes to the assessment of safety and efficacy of a phytomedicine
3.2. clinical trial
alt:[interventional study]
research study that prospectively assigns human participants to one or more interventions to evaluate the effects on health outcomes
3.3. randomized controlled trial
alt:[RCT]
clinical trial in which participants are allocated to intervention groups by chance (randomization)
3.4. observational study
research study in which participants are observed and outcomes measured without assignment of interventions by the investigator
3.5. systematic review
review that uses systematic methods to identify, select, and critically appraise relevant research, and to collect and analyze data from included studies
3.6. meta-analysis
statistical analysis that combines the results of multiple scientific studies
3.7. traditional use evidence
documentation of the historical use of a phytomedicine over one or more generations within a specific cultural context
3.8. well-established use
regulatory concept referring to a medicinal product with recognized safety and efficacy based on at least 10 years of use in a specific jurisdiction
3.9. efficacy
ability of a phytomedicine to produce a beneficial therapeutic effect under controlled conditions
3.10. effectiveness
degree to which a phytomedicine produces a beneficial effect under real-world conditions
3.11. safety profile
comprehensive summary of known and potential adverse effects, contraindications, and drug interactions associated with a phytomedicine
3.12. pharmacovigilance
science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or other drug-related problems
3.13. investigational product
phytomedicine being tested or used as a reference in a clinical trial
| Study type | Key features | Strengths/limitations |
|---|---|---|
Randomized controlled trial | Random allocation, control group, blinding | High internal validity; may have limited external validity |
Non-randomized controlled trial | Control group without randomization | Practical for some settings; potential for confounding |
Cohort study | Follows groups over time | Good for rare exposures; potential for confounding |
Case-control study | Compares cases with controls | Good for rare outcomes; recall bias |
Case series | Description of multiple cases | Hypothesis generation; no control group |
4. Evidence hierarchy
4.1. Levels of evidence
Evidence for phytomedicine safety and efficacy shall be classified according to a hierarchical system that reflects the relative strength of different evidence types.
| Level | Evidence type | Description |
|---|---|---|
Level I | Systematic reviews of RCTs | Meta-analyses and systematic reviews of randomized controlled trials |
Level II | Randomized controlled trials | Well-designed randomized controlled trials with adequate sample size |
Level III | Non-randomized controlled studies | Controlled studies without randomization, cohort studies |
Level IV | Real-world evidence (RWE) | Data from routine clinical practice, registries, electronic health records, post-market surveillance [Sherman R.E. et al.] |
Level V | Case series and case reports | Uncontrolled studies, case series, case reports |
Level VI | Traditional use evidence | Documented historical use, ethnobotanical records, traditional knowledge |
4.2. Evidence weighting
When evaluating the totality of evidence, the following factors shall be considered:
Study design (higher levels provide stronger evidence)
Methodological quality of individual studies
Consistency of findings across studies
Directness of evidence to the population and intervention of interest
Precision of effect estimates
4.3. Traditional use evidence
Traditional use evidence may be considered as supporting evidence when:
The phytomedicine has been used for a defined period (typically 30+ years)
The conditions of use (dose, route, population) are documented
Safety information is available from traditional use
The traditional preparation method is relevant to the modern product
Note | Traditional use evidence alone is generally insufficient to support efficacy claims in most regulatory jurisdictions, but may support safety and guide clinical research design. |
4.4. Real-world evidence
Real-world evidence (RWE) derived from routine clinical practice shall be considered as complementary to randomized controlled trial data, particularly for:
Safety signal detection in diverse populations
Long-term effectiveness assessment
Drug-herb interaction monitoring in clinical settings
Rare adverse event detection
Sources of real-world evidence include:
Electronic health record (EHR) databases
Disease and product registries
Pharmacy dispensing databases
Health insurance claims data
Post-market surveillance programs
Note | Real-world evidence requires careful methodological consideration to address confounding and selection bias. Regulatory acceptance of RWE varies by jurisdiction [Sherman R.E. et al.]. |
5. Study design considerations
5.1. Product characterization
5.1.1. Identity and quality
The investigational phytomedicine product shall be fully characterized, including:
Botanical identity (species, plant part, geographic origin)
Manufacturing process and quality control
Phytochemical profile (marker compounds, batch-to-batch consistency)
Specifications and certificate of analysis
Note | Poor product characterization is a common limitation of published phytomedicine clinical studies. |
5.1.2. Standardization
When applicable, the study product shall be standardized to defined marker compounds or active constituents.
5.2. Study population
5.2.1. Participant selection
The study population shall be defined by:
Inclusion criteria appropriate to the research question
Exclusion criteria that address safety concerns
Relevant demographic and clinical characteristics
5.2.2. Sample size
Sample size calculations shall be performed and documented, based on:
Expected effect size
Variability in primary outcome measures
Statistical power requirements
Significance level
5.3. Outcome measures
5.3.1. Primary outcomes
Primary outcomes shall:
Be clinically relevant to the indication
Be valid, reliable, and responsive to change
Be specified a priori in the study protocol
5.3.2. Secondary outcomes
Secondary outcomes may include:
Additional clinical measures
Quality of life assessments
Biomarkers
Safety outcomes
5.4. Control interventions
Control interventions may include:
Placebo (when ethically appropriate)
Active comparator (standard treatment)
No treatment (for pragmatic trials)
Dose comparison
Placebo control shall match the investigational product in appearance, taste, and smell where possible.
5.5. Study duration
Study duration shall be:
Appropriate to the indication and expected time to effect
Sufficient to detect both efficacy and safety signals
Justified in the study protocol
For chronic conditions, long-term safety data (6+ months) is typically required.
6. Quality assessment of clinical studies
6.1. Quality criteria
The methodological quality of clinical studies shall be assessed using validated assessment tools appropriate to the study design.
| Study design | Assessment tool |
|---|---|
Randomized controlled trials | Cochrane Risk of Bias tool, Jadad scale |
Non-randomized studies | Newcastle-Ottawa Scale, ROBINS-I |
Systematic reviews | AMSTAR 2, ROBIS |
6.2. Quality domains for RCTs
Quality assessment of randomized controlled trials shall address:
Random sequence generation
Allocation concealment
Blinding of participants and personnel
Blinding of outcome assessment
Incomplete outcome data
Selective reporting
Other sources of bias
6.3. Transparency requirements
To support quality assessment, clinical studies shall be:
Registered in a public trials registry before enrollment
Conducted in accordance with Good Clinical Practice (GCP)
Reported completely and transparently
Made available through open access when possible
6.4. Pharmacovigilance requirements
Adverse event monitoring for phytomedicines shall be conducted according to the requirements specified in this clause.
Note | The World Health Organization recommends integrating safety monitoring of herbal medicines into existing pharmacovigilance systems [Mhando L. et al.]. |
6.4.1. Spontaneous reporting
Spontaneous reporting systems shall capture adverse events associated with phytomedicine use:
All serious adverse events (death, life-threatening, hospitalization, disability, congenital anomaly) shall be reported within 15 calendar days
Non-serious adverse events shall be reported according to local regulatory requirements
Reports shall include: patient demographics, suspect product (with batch number and botanical identification), adverse event description, outcome, and concomitant medications
6.4.2. Signal detection
Signal detection for phytomedicine safety shall employ validated pharmacovigilance methods:
| Method | Description |
|---|---|
Proportional Reporting Ratio (PRR) | Compares proportion of specific adverse event for a product vs. all other products |
Reporting Odds Ratio (ROR) | Measures association between product and adverse event using case-control approach |
Multi-item Gamma Poisson Shrinker (MGPS) | Bayesian data mining algorithm for detecting signals in large databases |
Disproportionality analysis | Statistical comparison of observed vs. expected reporting rates |
6.4.3. Causality assessment
Causality assessment for adverse events associated with phytomedicines shall use standardized algorithms:
WHO-UMC causality categories (certain, probable, possible, unlikely, conditional, unassessable)
Naranjo algorithm (definite, probable, possible, doubtful)
Note | Causality assessment for herbal medicines presents unique challenges due to variability in product composition and limited documentation of concomitant use [Kongkaew C. & Phan T.H.D.]. |
6.4.4. Periodic safety reporting
Marketing authorization holders for phytomedicines shall submit:
Periodic Safety Update Reports (PSURs) at intervals specified by regulatory authorities
Risk Management Plans (RMPs) for products with identified safety concerns
Annual safety reports for products marketed under traditional use or dietary supplement regulations
6.5. Herb-drug interaction documentation
6.5.1. Mechanism-based assessment
Herb-drug interactions shall be evaluated based on pharmacokinetic and pharmacodynamic mechanisms:
| Mechanism | Examples and clinical significance |
|---|---|
Cytochrome P450 inhibition | Grapefruit juice (CYP3A4); Hypericum perforatum (CYP3A4 induction); reduced drug levels or increased toxicity |
P-glycoprotein transport | Panax ginseng (P-gp inhibition); altered drug absorption and distribution |
Pharmacodynamic synergism | Anticoagulant herbs + warfarin (increased bleeding risk); sedative herbs |
Pharmacodynamic antagonism | Stimulant herbs + antihypertensives (reduced efficacy) |
6.5.2. Documentation requirements
Clinical studies of phytomedicines shall document:
Potential herb-drug interactions based on known mechanisms
Concomitant medications used by study participants
Observed interactions during the study
Post-study monitoring for delayed interactions
[Bhatt A. et al.] (systematic review of herb-drug interaction mechanisms)
7. Reporting standards
7.1. Reporting guidelines
Clinical studies of phytomedicines shall be reported in accordance with recognized reporting guidelines:
CONSORT for randomized controlled trials
STROBE for observational studies
PRISMA for systematic reviews
TREND for non-randomized evaluations
7.2. Essential reporting elements
Reports of phytomedicine clinical studies shall include:
7.2.1. Product information
Complete botanical identification (species, authority, plant part)
Extract type and method of preparation
Drug-to-extract ratio (for extracts)
Standardization information (marker compounds and levels)
Dose and dosing regimen
Manufacturer and batch numbers
7.2.2. Study methods
Study design and justification
Participant eligibility criteria
Interventions for each group
Outcome measures and timing
Sample size calculation
Randomization and blinding methods
Statistical methods
7.2.3. Results
Participant flow (recruitment, allocation, follow-up, analysis)
Baseline characteristics
Results for primary and secondary outcomes
Harms and adverse events
Limitations
7.3. Data sharing
To support evidence synthesis and transparency:
Individual participant data should be made available where possible
Study protocols and statistical analysis plans should be published
Negative and inconclusive results should be reported
Bibliography
[Schulz K.F. et al.], CONSORT 2010 Statement: Updated guidelines for reporting parallel group randomized trials. BMJ 2010, 340, c332. doi:10.1136/bmj.c332
[Gagnier J.J. et al.], Reporting randomized, controlled trials of herbal interventions: an elaborated CONSORT Statement. Ann. Intern. Med. 2006, 144(5) pp. 364-367. doi:10.7326/0003-4819-144-5-200603070-00013
[Cheng C.W. et al.], CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration. Ann. Intern. Med. 2017, 167(2) pp. 112-121. doi:10.7326/M16-2977
[[[WHO2000,WHO General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine]]], World Health Organization, Geneva, 2000
[Mhando L. et al.], Pharmacovigilance and herbal medicines safety: A cross-sectional study of healthcare professionals' knowledge, attitudes, and practices. Front. Pharmacol. 2025, 16 p. 12860113. doi:10.3389/fphar.2025.12860113
[Kongkaew C. & Phan T.H.D.], Estimating adverse events associated with herbal medicines using pharmacovigilance databases: Systematic review and meta-analysis. JMIR Public Health 2024, 12 p. e63808. doi:10.2196/63808
[Bhatt A. et al.], Herb-drug interactions in oncology: Pharmacodynamic and pharmacokinetic perspectives. Front. Pharmacol. 2025, 16 p. 12232703. doi:10.3389/fphar.2025.12232703
[Sherman R.E. et al.], Real-world evidence: What is it and what can it tell us? N. Engl. J. Med. 2023, 375(23) pp. 2293-2297. doi:10.1056/NEJMsb1609216
[Santos J. et al.], Signals of adverse reactions to herbal medicines: A systematic review. Drug Saf. 2025, 48(7) pp. 653-672. doi:10.1007/s40264-025-01580-3
[Fasinu P.S. et al.], Herb-drug interactions: A critical exploration in modern healthcare. J. Med. Nat. Prod. 2025, 4(1) p. 100014. doi:10.53941/jmnp.2025.100014
[ICH E6(R2) Good Clinical Practice], International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, 2016
[Eich D. et al.], Clinical trials in phytomedicine: Challenges and opportunities. Phytomedicine 2015, 22(12) pp. 1061-1065. doi:10.1016/j.phymed.2015.08.007
[[[FWHO2000,WHO Guidelines on Developing Consumer Information on Proper Use of Traditional, Complementary and Alternative Medicine]]], World Health Organization, Geneva, 2000