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CLINICAL TRIALS OF TRADITIONAL HERBAL MEDICINES IN INDIA: CURRENT


STATUS AND CHALLENGES

Article  in  International Journal of Pharmacognosy · July 2014


DOI: 10.13040/IJPSR.0975-8232.IJP.1(7).415-421

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Singh et al., IJP, 2014; Vol. 1(7): 415-421 ISSN: 2348-3962

IJP (2014), Vol. 1, Issue 7 (Review Article)

Received on 17 March, 2014; received in revised form, 13 June, 2014; accepted, 29 June, 2014; published 01 July, 2014

CLINICAL TRIALS OF TRADITIONAL HERBAL MEDICINES IN INDIA: CURRENT STATUS


AND CHALLENGES

Harsharan Pal Singh *1, Sanchit Sharma 2, Shikha Baghel Chauhan 3 and Ishpreet Kaur 4

AIMIL Pharmaceuticals (I) Limited 1, Naraina, New Delhi, India


Department of Pharmacognosy, Jamia Hamdard University 2, Hamdard Nagar, New Delhi, India
Amity Institute of Pharmacy, Amity University 3, Noida, Uttar Pradesh, India
Delhi Institute of Pharmaceutical Sciences & Research 4, Pushp Vihar, New Delhi, India

Keywords: ABSTRACT: Traditional herbal medicines include herbs, herbal materials, herbal
preparations and finished herbal products that contains as active ingredients parts of
Clinical trials, Drugs and Cosmetic
plants, or other plant materials, or combinations. Clinical trials of traditional herbal
Act, Herbal drugs, Safety
medicines are carried out with herbal preparations only after standardization and
identification of markers to ensure that the substances being evaluated are always the
Correspondence to Author:
same. It is very important to assess the direct and indirect risks associated with
Harsharan Pal Singh
traditional herbal medicines. This can only be established once safety and efficacy of
Quality Control Executive herbal medicines are being proven during clinical trials. There are various concerns
AIMIL Pharmaceuticals (I) Limited over the clinical trial designs in India. It has been observed that during clinical trials
Naraina Industrial Area, various problems are being observed such as Batch to batch variation, use of placebo
New Delhi-110028, India instead of innovative product, in adequate quality control system, inadequate
requirement for the assessment of safety and efficacy for different types of herbal
E-mail:
medicines and difficulty in quantification due to complex nature of extract. This
harsharanpal.singh@gmail.com
review focuses on the current status of clinical trials of traditional herbal medicines
in India and an attempt has also been made to review the problems encountered
during conduction of clinical trials and suggestions and recommendations are also
provided to ensure that the clinical trials can be conducted with safety and efficacy.

INTRODUCTION: By definition, ‘traditional’ use Herbal medicine is the mainstay of about 75 - 80%
of herbal medicines implies substantial historical of the world population, mainly in the developing
use, and this is certainly true for many products that countries for primary health care 2. This is
are available as ‘traditional herbal medicines’. primarily because of the general belief that herbal
Ayurveda, Unani and Siddha are the medical drugs are without any side effects besides being
systems primarily practiced in India that has been cheap and locally available 3. According to the
known for nearly 5000 years. It includes diet and World Health Organization (WHO), the use of
herbal remedies, while emphasizing the body, mind herbal remedies throughout the world exceeds that
and spirit in disease prevention and treatment 1. of the conventional drugs by two to three times 4.
QUICK RESPONSE CODE The use of plants for healing purposes predates
DOI:
human history and forms the origin of much
10.13040/IJPSR.0975-8232.IJP.1(7).415-421 modern medicine. Many conventional drugs
originated from plant sources: a century ago, most
Article can be accessed online on: of the few effective drugs were plant based.
www.ijpjournal.com Examples include aspirin (willow bark), digoxin
(from foxglove), quinine (from cinchona bark), and
DOI link: http://dx.doi.org/10.13040/IJPSR.0975-8232.IJP.1(7).415-421
morphine (from the opium poppy) 5. Clinical trials

International Journal of Pharmacognosy 415


Singh et al., IJP, 2014; Vol. 1(7): 415-421 ISSN: 2348-3962

of traditional herbal medicines are carried out with authorizations for similar products. Although
herbal preparations after standardization and prolonged and apparently uneventful use of a
identification of markers to ensure that the substance usually offers testimony of its safety,
substances being evaluated are always the same. investigation of the potential toxicity of naturally
occurring substances may reveal previously
WHO Guidelines for Herbal Medicines
unsuspected problems. It was also recommended
In 1992, the WHO Regional Office for the Western
that regulatory authorities have the authority to
Pacific invited a group of experts to develop
respond promptly to new information on toxicity
criteria and general principles to guide research
by withdrawing or limiting the licences of
work on evaluating herbal medicines 6. This group
registered products containing suspect substances,
recognized the importance of herbal medicines to
or by reclassifying the substances to limit their use
the health of many people throughout the world,
to medical prescription. The guidelines stressed the
stating: ‘A few herbal medicines have withstood
need for assessment of efficacy including the
scientific testing, but others are used simply for
determination of pharmacological and clinical
traditional reasons to protect, restore, or improve
effects of the active ingredients, and labelling
health.
which includes a quantitative list of active
Most herbal medicines still need to be studied ingredient(s), dosage, and contraindications.8
scientifically, although the experience obtained
from their traditional use over the years should not Ethical Considerations in Clinical trials with
be ignored. As there is not enough evidence Herbal Products: WHO
All of the fundamental ethical principles of human
produced by common scientific approaches to
participation in research apply equally to herbal
answer questions of safety and efficacy about most
remedies and research involving these compounds.
of the herbal medicines now in use, the rational use
Consent must be obtained, subject selection must
and further development of herbal medicines will
be equitable, risks and benefits must be weighed
be supported by further appropriate scientific
and must be favourable to the potential participant,
studies of these products, and thus the development
and experimental design must be sound.
of criteria for such studies’.
Concerns that particularly apply to clinical trials
The document covered such topics as developing
with herbal products include:
protocols for clinical trials using herbal medicines,
 Product adulteration (has it been documented?)
evaluating herbal medicine research, guidelines for
 Interactions between herbal remedies and other
quality specifications of plant materials and
entities (rarely understood)
preparations, and guidelines for pharmacodynamic
 Reproductive and organ toxicity data (may be
and general pharmacological studies of herbal
minimal)
medicines and for toxicity investigations of herbal
medicines. WHO has also issued Guidelines for the  Prior dose finding (likely to be incomplete).
Assessment of Herbal Medicines 7. These The uncertainty in these areas must be clearly
guidelines defined the basic criteria for the disclosed to all concerned, particularly during the
evaluation of quality, safety and efficacy of herbal informed consent process. In many regions of the
medicines with the goal of assisting national world, strong belief that herbal medicines will be
regulatory authorities, scientific organizations and beneficial and safe may introduce bias, which can
manufacturers in assessing documentation, be minimized by careful attention to study design
submissions and dossiers in respect of such including appropriate control groups. Where
products. possible, the community from whom the medicine
originates should be consulted during the course of
It was recommended that such assessments take
the research, and the results and benefits of the
into account long-term use in the country (over at
least several decades), any description in the research should be shared with this community.
medical and pharmaceutical literature or similar As in other types of research, a well trained, ethical
sources or documentation of knowledge on the investigator is the best assurance of patient safety
application of a herbal medicine, and marketing in research. Therefore, skilled clinicians should be

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Singh et al., IJP, 2014; Vol. 1(7): 415-421 ISSN: 2348-3962

chosen as investigators to assure prompt medical posts are occupied by physicians who
recognition and appropriate treatment of any belong to the traditional systems.11
observed adverse event or worsening of a pre-
Legal Status of Traditional Herbal Medicines in
existing condition.
India
Ethics committees must apply the same vigilant In India, traditional medicines are governed by the
attitude towards herbal studies as they do towards Drugs and Cosmetics Act of 1940 and the Drugs
conventional treatment protocols.9 and Cosmetics Rules of 1945. They regulate the
import, manufacture, distribution and sale of drugs
Market Importance and Use of Herbal
and cosmetics. In 1959, the Government of India
Medicines: Indian Scenario
recognized the traditional Indian systems of
In India, a great deal of folk knowledge exists
medicine and amended the Drugs and Cosmetics
among ordinary people about the traditional use of
Act to include drugs which are derived from
herbal medicines. It is difficult to quantify the
traditional Indian medicine.
market size of the traditional Indian systems since
most practitioners formulate and dispense their own No products derived from traditional systems may
recipes. The present annual turnover of products be manufactured without a licence from the State
manufactured by large companies is estimated at Drug Control Authorities. Patent and proprietary
approximately US $ 300 million, compared to a medicines derived from the traditional systems
turnover of approximately US $ 2.5 billion for must contain ingredients which are mentioned in
modern drugs. According to a study on the attitude the recognized books of the above systems, as
of modern medicine practitioners towards specified in the Drugs and Cosmetics Act. The
Ayurvedic products, general practitioners are government is advised by a special committee and
relatively unfamiliar with Ayurvedic products even an advisory board for Ayurvedic, Siddha and Unani
though some are prescribed. They are willing to try drugs. Pharmacopoeia committees have been
an Ayurvedic product if its efficacy is scientifically constituted to prepare pharmacopoeias for all these
proven, and would try. systems.10,11
Ayurvedic products if no modern medicinal In 1993, an expert committee appointed by the
remedies were available. People use self- Indian government developed guidelines for the
medication for minor ailments such as cough, cold, safety and efficacy of herbal medicines which were
diarrhoea and stomach problems. Patent and intended to be incorporated into the Drugs and
proprietary Ayurvedic medicines are sold over the Cosmetics Act and rules. It was proposed that no
counter in pharmacies. These products appear to new herbal medicines other than those authorized
represent a major share of branded traditional by the licensing authorities be allowed to be
products in India. manufactured or marketed, except for those
Nevertheless, systems like Ayurveda still need to mentioned in and manufactured in compliance with
gain an empirical support of modern medical the formulae given in the "authoritative" books for
science to make them credible and acceptable for Ayurveda, Siddha and Unani herbal medicines.
all. An innovative research effort to define the A manufacturer of a new herbal medicine must
advantages of traditional systems of medicine with include safety data and appropriate efficacy data in
respect to their safety and efficacy could result in a the marketing authorization application. Herbal
better utilization of these complementary systems preparations are defined as natural products in
of medicine.10 which the predominant active constituents are of
In India, there are currently about 2,50,000 plant origin. A classification for herbal medicines
registered medical practitioners of the Ayurvedic was proposed depending on their market
system (total for all traditional systems: availability, and the nature of the herbs:
approximately 2,91,000), as compared to about  Category 1: already in use for more than 5
7,00,000 of the modern medical system. In every years
Indian state, about one-third of the governmental  Category 2: in use for less than 5 years
 Category 3: new medicines.

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Singh et al., IJP, 2014; Vol. 1(7): 415-421 ISSN: 2348-3962

The classification of herbal medicines depends on Some of the recommendations are:


whether they contain processed or unprocessed  Clinical trials should be carried out with
parts of plants and whether they contain potentially herbal preparations only after
poisonous plants. Requirements for safety and standardization and identification of
efficacy vary according to the classification and markers to ensure that the substances being
market availability of the product. Depending on evaluated are always the same.
the nature of herbs and market availability,  Plants and herbal remedies should be
different requirements exist for submission of prepared strictly in the same way as
clinical trial data and toxicity data.11 described in the literature while
incorporating GMP norms for
In 2001, the Central Drugs Standard Control
standardization.
Organisation of Directorate General of Health
 For herbal remedies, Phase 1 studies
Services has recently issued GCP guidelines. These
must be undertaken to check
guidelines recommend the approach to clinical
Maximum tolerarated dose (MTD) &
trials of herbal remedies and medicinal plants.12
Early Measurement of Drug activity.
The guidelines divide the herbal products into
 If there are reports suggesting toxicity or
different categories based on the whether the use
when the herbal preparation is to be used
and formulation of product are as per the traditional
for more than 3 months, toxicity studies (4-
medicine literature or are not as per the traditional
6 weeks toxicity study in 2 species) are
documentation.
needed for phase 2 trials.
 For the herbal remedies and medicinal  For Phase 3 trial toxicity studies (4-6 weeks
plants that are to be clinically evaluated for toxicity study in 2 species) are needed.
use in the Allopathic System and which  Ethical guidelines (patient information,
may later be used in allopathic hospitals, the informed consent, protection of vulnerable
procedures laid down by the office of the populations etc) for biomedical research
Drugs Controller General of India for should be followed.
allopathic drugs should be followed.  Clinical trials should to be approved by the
 When an extract of a plant or a compound appropriate scientific and ethical
isolated from the plant has to be clinically committees of the concerned Institutes.
evaluated for a therapeutic effect not  Clinical trials should be carried out only
originally described in the texts of when a competent Ayurvedic, Siddha or
traditional systems or, the method of Unani physician is a co-investigator. 11,12
preparation is different, it has to be treated
With the introduction of Drugs & Cosmetics Rule
as a new substance or new chemical entity
158 B since August 2010, the requirement of proof
(NCE) and the same type of acute, sub
of effectiveness for licensing of patent or
acute and chronic toxicity data will have to
proprietary ASU (Ayurvedic, Siddha, and Unani)
be generated as required by the regulatory
medicine has necessitated the development of
authority before it is cleared for clinical
guidelines of Good Clinical Practice. The quality
evaluation.
concerns of ASU products in terms of their safety
 An extract or a compound isolated from a
and therapeutic efficacy can be readdressed, if the
plant, which has never been in use before
clinical research generates quality data, acceptable
and has not ever been mentioned in ancient
to regulatory authorities for product registration or
literature, should be treated as a new drug,
approval for marketing, especially for products
and therefore, should undergo all regulatory
based on non-classical or non-generic
requirements before being evaluated
formulations.12,13
clinically.
In March 2013, The Department of AYUSH,
The document also provides general guidelines on
Ministry of Health & Family Welfare introduced
clinical trials of herbals, toxicity studies, need for
Good Clinical Practices guidelines for conduction
standardization, and compliance with GCP in all
of clinical trials for Ayurveda, Siddha & Unani
clinical trials.

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Singh et al., IJP, 2014; Vol. 1(7): 415-421 ISSN: 2348-3962

medicines. The document provides general the assessment of safety in a clinical trial. Quality
guidelines on clinical trials of herbals, toxicity has to be assured at all stages – herbal raw
studies, need for standardization, and compliance materials, processing of herbals and finished herbal
with GCP in all clinical trials.13 medicines.
Current Challenges for Herbal Medicines Evidence of Clinical Efficacy Scientific evidence
There are several regulatory concerns in relation to from randomized clinical trials is only strong for
research applications and commercialization of many uses of acupuncture, some herbal medicines
traditional herbal medicines. and for some of the manual therapies.17 Only a
small fraction of the thousands of medicinal plants
Standardization of herbal drugs
used worldwide has been tested rigorously in
For safe and effective use of herbal drugs,
randomized, controlled trials. Even if the animal
consistency in composition and biologic activity
studies or anecdotal clinical experiences are
are essential requirements. However, herbal drugs
promising and use of an herb is widespread, such
frequently fail to meet this standard, as there are
observations cannot predict the results of well
problems such as 1) difficulties in identification of
designed randomized, controlled trials.
plants, 2) genetic variability, 3) variations in
growing conditions, 4) diversity in harvesting A recent review concluded that evidence-based
procedures and processing of extracts, and 5) the studies on the efficacy and safety of traditional
lack of information about active pharmacologic Indian medicines are limited.18 The data available is
principles.14 mostly experimental or in animals.
The use of chromatographic techniques and marker Most trials do not report hard efficacy endpoints
compounds for the standardization of herbal and duration of observation periods is generally
products can ensure batch-to-batch consistency; short. The clinical relevance of the observed effects
however, this does not ensure consistent is not always clear.19 For instance, most Indian
pharmacologic activity or stability. The Lack of trials of hepatoprotective agents are open and
standardization of herbal drugs would be a serious uncontrolled. As most acute liver conditions have a
problem for a researcher as the researcher would natural recovery, it is difficult to link the
not be able to rely on commercially available improvement to the herbal product. 20
herbal products for his research studies. A fundamental problem in all clinical research of
Quality of herbal preparations herbal medicines is whether different products,
If an herbal remedy is effective, quality assurance extracts, or even different lots of the same extract
is needed to ensure that the product has the are comparable and equivalent. For example,
expected effects. Even in the absence of data on Echinacea products can contain other plant
efficacy, quality assurance is important, as quality extracts; use different plant species (E. purpurea,
is a critical determinant of safety as well.15 pallida or angustifolia), different parts (herb, root,
Adulteration of plants is serious problem. Some of both), and might have been produced in quite
the common adulterants are: botanicals, toxic different manners (hydro- or lipophilic extraction).
metals, microorganisms, microbial toxins, Even different species may be known by the same
pesticides, and fumigation agents. The drugs most name in local language. Brahmi refers to Centella
frequently found were ephedrine, asiatica and Bacopa monniera.
chlorpheniramine, methyltestosterone, and The herbal industry is not required to conduct
phenacetin; 10 to 15 percent contained lead, clinical trials, and the industry professionals argue
mercury, or arsenic. that it would be not be possible to recover the high
The incidence of heavy metal contamination is not research costs, as herbal products cannot be
known, but one study showed that 64% of samples patented as easily as new chemical entities.
collected in India contained significant amounts of Nevertheless, randomized, controlled trials are the
lead (64% mercury, 41% arsenic and 9% best way to demonstrate the efficacy of any
cadmium).16 This can cause serious harm to medicine, herbal or conventional.15
patients taking such remedies and could confound
Safety Concerns - Drug Interactions

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Singh et al., IJP, 2014; Vol. 1(7): 415-421 ISSN: 2348-3962

Herbal medicines are generally considered and efficacy for different categoriszed herbal
comparably safer than synthetic drugs. While this medicines to reduce cost and expenditure.
may be probably correct, case reports show that
severe side effects and relevant interactions with CONCLUSION: The challenges can be overcome
other drugs can occur. For instance, the herb by applying most recent methodologies and
Ephedra marketed as a dietary aid, led to at least a guidelines for clinical trials. With modern
dozen deaths, heart attacks and strokes. Other well- manufacturing techniques, and WHO approved,
known safety issues have been hepatotoxicity of ISO certified units; drug can be manufactured by
kava and renal effects of aristolochic acid.21 masking the strong smell and fine coating blinds
Besides, drug interactions of herbal drugs are of a the typical colors and tastes of herbs. This
serious concern. For example, hypericum extracts facilitates blinding methods for clinical trials.
can decrease the concentration of a variety of other Planning of scientific clinical study design is very
drugs by enzyme induction. much essential for success of any clinical trial
which is applicable here. To obtain reliable clinical
Lack of regulatory standards regarding the efficacy trial results for herbal medicines, double-blind
and safety of herbal products did not arouse much experiments should be applied with enough patients
concern in the past, as these products were often selected, ideally using the standard of clinical trial
perceived as so safe that even if they were for new drug development.
ineffective, little harm resulted.21 However, the
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How to cite this article:


Singh HP, Sharma S, Chauhan SB and Kaur I: Clinical Trials of Traditional Herbal Medicines in India: Current Status and Challenges. Int
J Pharmacognosy 2014; 1(7) 415-421: .doi: 10.13040/IJPSR. 0975-8232.IJP1(7). 415-421.

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