Herbal Clinical Trial: Opportunity & Challenges

Dr. Jarir At Thobari, DPharm, PhD

1Dept. Pharmacology & Therapy Div. Pharmacoepidemiology, Pharmacovigilance & Pharmacoeconomic
2Clinical Epidemiology and Biostatistic Unit (CEBU) 3Indonesia Cochrane Center (ICC)
4Center for Child Health/Pediatric Research Office (CCH/PRO)
5Regional Training Center (RTC) for Good Clinical Practice WHO/TDR
6Center for Bioethics and Medical Humanity (CBMH), 7UNESCO Chair for Bioethics
Faculty of Medicine, Public Health & Nursing Universitas Gadjah Mada
Global Herbal
Medicinal
Product Market

2021 2022 2023 2024 2025 2026 2027 2028

Herbal Medicinal Products Market – Global Industry

Trends and Forecast to 2028 | Data Bridge Market
Research
Product Registration
in Indonesia:

Number of products
registered in the last
5 years
Data per January 2021
Source www.pom.go.id

Guide to Product Registration in Indonesia Through BPOM (cekindo.com)

Worldwide research on
medical plants and
publication
Salmerón-Manzano E, et al. Worldwide Research Trends on Medicinal
Plants. Int. J. Environ. Res. Public Health 2020, 17(10), 3376
Salmerón-Manzano E, et al. Worldwide Research Trends on Medicinal
Plants. Int. J. Environ. Res. Public Health 2020, 17(10), 3376
Three pillars of ideal herbal drug and their rational use

QUALITY

Appropriate use of
herbal drug

QUALITY
SAFETY EFFICACY
ACCESSABILITY
AVAILABILITY
SAFETY EFFICACY

6
Clinical studies on the standardized formulated drug

Well-established, randomized
controlled clinical trials provide the The chemical complexity of
highest level of evidence for efficacy. herbal medicines causes
multiple effects in humans
which must be tested only
Such studies facilitate the acceptance throughout clinical trials.
of herbal medicines in different
regions and in people with different
cultural traditions.
 Financial

Clinical trials Product

standardization Ethical
Herbal Drugs (quality control)

- Challenges

Design of Regulatory
the study Requirement
Ethical Aspect - Risk Benefit Ratio

Risk assessment is one of the most important considerations for the ethical
acceptability of research involving human subjects.

In a risk–benefit analysis, existing data on toxicity, dosage form, and potential

adverse effects of proposed herbal drugs under investigation are required to
support and justify the conduct of clinical trials.

Any herbal drug trials should be conducted only if the risks to trial subjects are
minimized and reasonable in relation to anticipated benefits.
 Reduce
Quality control &
adulterations with
standardization
substandard drugs

Need of Improper
Scientific
quality authentication
validation of the
therapeutic claims
control
Customer
Identity, purity,
satisfaction and
efficacy and safety
confidence
 Constraints in quality control of herbal drugs

Main Dependence on Herbal Pharmacopoeia?

Regulatory Aspects Wild Sources

Adulteration/ Lack of Public Test Houses

Substitution
Constraints in Quality
Control of Herbal Drug
Products
No Certification of Raw Lack of Safety Evaluation
Materials Facility

Pharmacovigilence Data Lack of Trained Man Poor Investment In R&D Of

Not Collected Power Herbal Medicine
Ishikawa cause and effect diagram for content variation of herbal drugs

Shinde M.V., Dhalwal K., Potdar K., Mahadik K. Application of quality control principles to herbal drugs. International Journal of Phytomedicine 1(2009); p. 4-8.
Some Concerns of Herbal Trials

Methodological quality is variable

Quality of the trial drug has to be tested for batch-

to-batch uniformity of the active constituents
Source, processing and final composition of the
herbal product
Herbal trials generally use placebo and not an active
comparator
RCT (randomized controlled clinical trial)

Randomized Randomisation

Inclusion

Controlled Procedure

Outcome

Intervention
Clinical Trial
Vs. control group
Define inclusion criteria of the
trial participants
• The inclusion criteria can be based either on modern
medicine or herbal medicine diagnosis. The disease criteria
can be different in herbal and modern medicine approach.
• Therefore, difficult to generate a homogenous group of
subjects as per the diagnosis of herbal medicine.
• Jonas and Linde have devised a “double classification
method” where subjects are primarily diagnosed using
modern diagnostic criteria and then are classified according
to the traditional system.
• Treatments are given according to traditional classification
and outcomes are evaluated by criteria for both the
systems

Jonas WB, Linde K. Conducting and evaluating clinical research on complementary and alternative medicine. In: Gallin JI, editor. Principles and
Practice of Clinical Research. San Diego, CA: Academic Press; 2002. p. 401-26.
 Other issues in Herbal Trial

Combined use of an
herbal medication and Adequate doses of both
Study should be
a conventional rug herbal drug and active
adequately powered
considered in clinical comparator to be used
trials
 Outcome measures
• It should be able to capture or detect the effects
conferred by an investigational herbal drug.
• The outcome measures may likely differ from those
used in synthetic drug trials as some constructs may
not be meaningful in a traditional herbal medicine
Outcome and perspective
Sample size Calculation of sample size
• Sample size is important in conducting a clinical study.
• Bian et al. evaluated 167 studies and found that only
0.6% RCTs conducted a proper sample size calculation

Koonrungsesomboon, N., et al. Ethical considerations and challenges in herbal drug trials with the focus on scientific validity and risk assessment. Phytotherapy
Research. 2020;1–7. Bian ZX, et al. Improving the quality of randomized controlled trials in Chinese herbal medicine, part I: Clinical trial design and methodology.
Zhong Xi Yi Jie He Xue Bao 2006;4:120-9.
Selection control

• Controls are selected such that they closely match with the intervention
group as comparator similarity is essential if the trial is intended to
provide the evidence of a specific effect of the herbal medicine.
• Controls should be standardized for factors such as
• color
• odor
• duration
• frequency of intake
• credibility of the treatment to the patient
• physical situation in which treatments are administered
Blinding

• In randomized clinical trials (RCT), blinding is a gold standard

that eliminates bias and isolates placebo effects.
• Double-blinded which means neither the investigator nor
the subject knows about the treatment allotment.
• It is challenged to maintain double-blind, as herbal
treatment involves multidimensional treatment approach
involving counseling, listening, explaining, lifestyle, and
dietary advice as well as prescribing herbal medicines.
• Single blinding can be done in such interventions, where the
investigator but not the patient knows the treatment
allocation
 Fig 2. Summary of the Risk of bias assessment for each included trials.

Cao H, Mu Y, Li X, Wang Y, Chen S, et al. (2016) A Systematic Review of Randomized Controlled Trials on Oral Chinese Herbal Medicine for
Prostate Cancer. PLOS ONE 11(8): e0160253. https://doi.org/10.1371/journal.pone.0160253
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160253
Evidence-Based Complementary and
Alternative Medicine Volume 2013
 Pragmatic Trial

Superior or Superior in
Superior to
non-inferior to addition to other
placebo
standard treatment

Efficacy Effectiveness
Specific effect Overall effect

Explanatory study Pragmatic study

Homogenous patient group Heterogenous patient group
Single intervention Also, complex intervention

High internal validity High external validity

Flower A., et al., Guidelines for randomised controlled trials investigating Chinese herbal medicine.
Journal of Ethnopharmacology 2012; 140(3): 550-554. Adami G, et al., Pragmatic Clinical Trials in
Osteoporosis. Current Osteoporosis Reports 2019;17(6)
 Matching a research question with an
appropriate methodology
Research Question Methodology
What is the efficacy of HM for a specific disease or
Placebo-controlled, double-blind, RCT
condition?
What is the effectiveness of HM in real world
Pragmatic randomised trial
practice?
Observational study-longitudinal survey
Are there side effects from HM?
Case controlled study
What is the patient's experience of taking HM? Qualitative research
Patient registries
Which conditions seem to respond well to HM? Observational study
Cross sectional survey of practitioners
What are the active ingredients of a particular herb? Laboratory experimentation
What is the economic cost of HM for treating a
Health economic evaluation
disease?
Another challenges
 Economic Evaluation
Technology Development Technology Adoption
++Approval Stage++ ++Patient Access Stage++

Macro Econ
Macro Econ
(growth)
(growth)
Conventional 3 Hurdles 4th Hurdle 5th Hurdle
6th Hurdle

Element CEA, CUA, and CBA BIA ROI

Concept Efficiency (value for money) Affordability Economic

Purpose Efficiency of the selected technology (new Financial impact of technology (alternative); Economic impact of
or existing) [Cash-flow] investment

Perspective Societal/payer Payer Country

Outcome Included QALY Excluded QALY ROI

Cost Opportunity Cost Financial Cost % econ growth

End-point ICER Budget change Econ Growth

25
CONSORT – Herbal Intervention
 Take Home Messages

Herbal medicine has potentially big market in many countries. It is needed strategic plan to
improve R&D for herbal drugs by increase capacity of researcher, networking and
collaboration

Clinical trial is important to assess safety and efficacy of the herbal drugs, and RCT is still the
best design to evaluate the efficacy and safety, but many challenges could be faced conducting
the trial such as standardization product, trial design, ethical and financial aspects.

Pragmatic trial is alternative design to evaluate the effectiveness Herbal medicine, and other
methodological design to address other research question. Economic evaluation is the 4th
hurdle to assess cost-effectiveness of the product to implement in the health care policy.
THANK YOU