|SYMPOSIUM: GASTROENTROLOGY & HEPATOLOGY-III
|Year : 2015 | Volume
| Issue : 4 | Page : 329-333
Challenges and guidelines for clinical trial of herbal drugs
Abida Parveen1, Bushra Parveen2, Rabea Parveen2, Sayeed Ahmad2
1 Department of Academics and Research, Fortis Escorts Heart Institute, New Delhi, India
2 Bioactive Natural Product Laboratory, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India
|Date of Submission||11-Apr-2014|
|Date of Decision||03-Jan-2015|
|Date of Acceptance||15-Feb-2015|
|Date of Web Publication||23-Oct-2015|
Bioactive Natural Product Laboratory, Faculty of Pharmacy, Jamia Hamdard, New Delhi
Source of Support: None, Conflict of Interest: None
| Abstract|| |
World Health Organization (WHO) has defined herbal medicines as finished labeled medicinal product that contain an active ingredient, aerial, or underground parts of the plant or other plant material or combinations. According to a report of WHO, about 80% of the world population is reported to rely on traditional medicine for their primary health care needs. Even in the developed countries, complementary or alternative medicine is gaining popularity. A report of a global survey on national policy on traditional medicine and regulation of herbal medicines indicated that about 50 countries including China, Japan, and Germany already have their national policy and laws on regulations of traditional medicines. Herbal drugs possess a long history of its use and better patient tolerance. These are cheaper and easily available in countries like India due to rich agro culture conditions. However, reckless utilization of resources threatens the sustainability of several plant species. Traditional medicines are governed by the Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945. In 1959, the Government of India amended the Drugs and Cosmetics Act to include drugs that are derived from traditional Indian medicine. In 1993, the guidelines for the safety and efficacy of herbal medicines developed by an expert committee directed that the procedures laid down by the office of the Drug Controller General of India for allopathic drugs should be followed for all traditional and herbal products to enter into clinical trials for any therapeutic condition. However, there are certain loop holes in the clinical trials of herbal drugs as the lack of stringent bylaws and regulations. Hence, a deep insight of important challenges and major regulatory guidelines for clinical trial of herbal drugs and botanicals is discussed in the present communication. There is lack of scientific evidence to evaluate safety and efficacy of herbal drugs. The quality of the trial drug has to be tested for batch-to-batch uniformity of the active constituents. It is very difficult to have active and control groups with identical color, smell and taste of the herbal drug, which cannot be imitated while manufacturing a placebo. These challenges can be reduced or overcome by applying most recent methodologies and guidelines for clinical trials. Since the quality control of herbal medicines is complicated and difficult, relevant and appropriate requirements should be established for the assessment of safety and efficacy for different categorized herbal medicines to reduce cost and expenditure. And, efforts should be made for the integration of traditional medicine into national healthcare systems. Different challenges and regulatory guidelines discussed for the clinical trial of herbal drugs will be useful for various industries for considering it before going ahead for clinical trial of their product.
Keywords: Clinical trial, herbal drugs, regulatory guidelines
|How to cite this article:|
Parveen A, Parveen B, Parveen R, Ahmad S. Challenges and guidelines for clinical trial of herbal drugs. J Pharm Bioall Sci 2015;7:329-33
The enriched culture and tradition of India has ushered upon us a plethora of endogenous flora, which among various utilities have also been used for medicinal purposes. Herbal medicines (phytomedicines) are closest to the conventional therapy approach than any other traditional or alternative medicine approaches. Based on the origin, evolution and the forms of current usage, herbal medicines have been divided into four categories, including indigenous herbal medicines, herbal medicines in systems (Ayurveda, Unani, and Siddha), modified herbal medicines and imported products with a herbal medicine base herbal medicines are prescribed by physicians across the globe as adjuvant or adjuncts with modern drugs and are dispensed or supplied primarily by pharmacists. Among developed countries, only USA has such legislations that consider herbs as "dietary supplements" and has eliminated them from medical scene.
Herbal medicines have several chemical constituents (phytoconstituents) which are known for their pharmacological effects on the body and are used since many centuries. The widespread and global acceptance and utilization of herbal medicines is suggestive of their safety and efficacy. However, the lack of assurance of safety and efficacy of herbal medicines is to a large extent levied upon insufficient pharmacokinetic, pharmacological and clinical data on the majority of herbal medicinal products. The wide gap in meeting the legislative requirements for research on herbal drugs further adds to the dilemma of regulation of herbal drugs. The critics of herbal medicines from all over the world have been eye opening for herbal practitioners. Although clinical trials were then been undertaken, still a wide road is to be covered to meet the level of evidence-based medicines at the international platform, Kumar in a lecture at Abuja, Nigeria, defined "clinical trial" as "a carefully designed and controlled research, in which humans receive a drug (or some other intervention), usually for the purpose of determining safety or efficacy, and the study may be divided into phases." A clinical research can initiate only after collection of relevant preclinical data on the intervention and grant of due approval from the relevant Health Authority/Ethics Committee about the design and objective of the study.
The present review thus focuses on the challenges of the clinical research of herbal medicines as well as the regulatory issues concerning herbal medicines.
| Clinical Research on Herbal Drugs: A need|| |
Herbal products have become an important and indispensable part of public healthcare around the world. Various surveys on traditional and alternative medicine have highlighted their widespread use. However, in order to further widen their forum of acceptance, clinical trials of these herbal products should be encouraged. To prove the efficacy of in clinical trials, it is advised to use single and consistent batches of formulations. Although herbal practitioners and believers do not require clinical trials, for its large scale endorsement and survival at the international market alongside modern medicines, it has become need of the hour.
| Clinical Research on Herbal Drugs: Challenges|| |
Research on herbal drug poses several challenges that need to be addressed. These include issues such as those related to the financial, ethical, product standardization (quality control), the design of the study and the regulatory requirements before filing an investigational new drug for conducting large phase III trials. In 2005, World Health Organization (WHO) issued operational guidelines regarding regulatory requirements needed to support clinical trials of herbal products.
It is advocated that the inclusion criteria can be based either on modern medicine or herbal medicine diagnosis. The understanding of the disease, and hence the disease criteria can be different in herbal and modern medicine approach. Therefore, it becomes difficult to define inclusion and exclusion criteria and hence to generate a homogenous group of subjects as per the diagnosis of herbal medicine. For this case, 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.
The outcome of the treatments in herbal medicine is dependent largely on the patient's participation. The traditional medicine fully utilizes the placebo effects as in providing patients' psychosocial support along with physical treatments in order to maximize the nonspecific factor that play an active role in the success of any practice. The treatments in herbal medicines are complex consisting of mixture of active components and also the specification regarding their administration. Therefore, the success of herbal treatment outcome depends on patient's will and motivation to complete the treatment. However, these factors can be minimized by application of blinding and randomization.
It is believed that randomization may eliminate the practice of preferences given to the subjects to select a treatment of choice. Brewin and Bradley therby proposed an approach called partial randomization whereby patients are asked about their choice and are given treatment preference of their choice while those who do not express a preference are randomized.
In randomized clinical trials (RCT), blinding is a gold standard that eliminates bias and isolates placebo effects. RCTs are usually double-blinded which means neither the investigator nor the subject knows about the treatment allotment. But in case of herbal medicines, it is impossible 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. Therefore, single blinding can be done in such interventions, where the investigator but not the patient knows the treatment allocation.
Another challenge involved in the RCT of herbal drugs is the selection of controls. 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, and credibility of the treatment to the patient and physical situation in which treatments are administered. However in certain natural products such as ginger, which has a peculiar odor, selecting a matching control is an uphill task.
Calculation of sample size is important in conducting a clinical study. Bian et al. evaluated 167 studies and found that only 0.6% RCTs conducted a priority sample size calculation.
The need to maintain occupational standardization has been realized. This is more evident in trials of herbal products where the therapist has an active role to play. The practitioners may feel uncomfortable with the protocol, and they may like to provide best therapeutic practice and thus protocol violations may occur. This therapist variability can be reduced by providing treatment manuals detailing the precise procedures to be followed.
Herbal medicines are individualistic in approach and may not be standardized as a treatment for a population. Moreover, the firm faith and belief may likely to influence the outcomes in trials. Baseline assessments of various psychological factors such as personality and mood must be carried out. Another concern is the problem of drop-in's and sample contamination. The investigators should vigilantly monitor their trial subjects whether they seek out herbal products outside the specified protocol.
| Regulatory Status of Herbal Drugs Research|| |
About 80% or even 90% of the population depend on herbal drugs for most of their primary healthcare needs. But it is also a fact that in these populations, the herbal drugs are not regulated by the state. It was reported "that about 80% of people in developing countries depended on herbs but contributed only 7.2% to the trade in 1999. By contrast, the developed nations, where people relied less on herbs, contributed 55.2% Asia, less Japan and South Korea, contributed 37.6%." These vast difference can be attributed to the regulation of herbal drugs in developed countries where herbal drugs are produced and utilized in accordance with good manufacturing practice (GMP) and good clinical practice, respectively. In Asian countries like China, India, and Korea, traditional is treated with same respect as modern pharmaceutical and are also included in the national health scheme. From 1986, the approval process for traditional medicines included approval for clinical trial and approval for marketing. For drug registration application, the data to be submitted include general product data, pharmaceutical data, pharmacological/toxicological data, and clinical data. From 1995, it became mandatory for manufacturers and marketers to be certified by the local drug regulatory authorities. Much stress was laid on GMP and good supplies practices for registration and certification.
WHO 1993 guidelines stated that the responsibility of quality assurance of herbal medicinal products has to be shared equally by manufacturers and regulatory bodies. It is the responsibility of regulatory authorities to establish guidelines on diverse aspects of quality assurance, dossiers and data evaluation and evaluation of postmarketing compliance of products with the specifications set out by the producers as well as compliance with GMP.,,
It is of utmost importance that the manufacturers firmly adhere to good agricultural and collection practices (GACP), GMP and good laboratory practice standards, establish appropriate specifications for their products, intermediates and starting materials and gather a complete documentation on pharmaceutical development and testing. The producers must keep pace with the current knowledge with regard to manufacturing and marketing.,
In WHO summit in 2000, several recommendations were put forth for quality control and cultivation of raw materials of herbal formulations. These recommendations included the formation of a sub-committee on GACP to facilitate the availability of good quality herbal medicines to the market by giving training and advice to small producers and farmers. To push on the implementation of GACP, incentives can be given to producers of botanical raw materials. These include giving technical and logistic support in the selection of appropriate sites for the agricultural production, providing seeds and seedlings, selecting fertilizers and pesticides, providing or giving advice on machinery for harvesting, and primary processing.
The national drug regulatory authority must ensure issue of license for importers, wholesalers, manufacturers and assemblers of herbal medicinal. As of now, the dealers of imported herbal medicinal products need to apply for one or more of the licences depending on the type of business involved, such as licence of importers, wholesalers, manufacturers, and assemblers.
Quality control ensures quality of the products by following well-structured and standard specifications. Such information about standard specifications can be found in official pharmacopeias, monographs, handbooks, etc. To check the quality of herbal products, various analytical techniques may be used. While choosing analytical methods, factors such as validity, precision, accuracy, and robustness of the method must be considered. With the advent of sophisticated techniques such as high-performance liquid chromatography, gas chromatography (GC), and GC-mass spectrometry (MS), it is possible to identify as well as quantify the test substance.
The registration of herbal products require detailed information of the herbal medicinal products including list of ingredients, full product formula for imported herbal-based medicinal products, particulars of manufacturer(s) and assembler(s), manufacturer's licence or certificate from the drug regulatory authority, brand name of product, dosage form, indications, dosage, mode of administration, duration of use, adverse effects, contraindications, warnings, precautions, and major drug interactions, if possible, date of manufacture, expiry date of product, lot/batch number, and storage condition.
Pharmacovigilance centers for herbal products are requiredto assess and collect information about the safety and efficacy of herbal products through monitoring adverse drug reactions.
Of the 11 member countries in the South-East Asia region, there are only four with national systems for monitoring the safety of traditional medicinal products. Therefore, it calls for an urgent need to national system for monitoring safety of herbal medicinal products.
| Steps in Clinical Research of Herbal Drugs|| |
The minimum requirement for reviewing the safety requirement of herbal drugs depends on the type of disease [Table 1].
|Table 1: Summary of the efficacy data requirements for the three types of disease and conditions|
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- Acute disease: Diseases that have a rapid onset and a relatively short duration
- Chronic disease: Diseases that have a slow onset and last for long periods of time
- Health condition: Problems related to health conditions are those which, with time, could recover spontaneously, even without any medical intervention, e.g. loss of appetite, hay fever, menopause, etc.
| Application of the Principles of Pharmacodynamics to Herbal Drugs|| |
The principles of pharmacodynamics when applied to herbal drugs invariably lead one of the following three scenarios: (i) Herbal drugs whose efficacies have been demonstrated - their active principles are known and their doses are more or less established; (ii) herbal drugs whose efficacies are probable, but have not been clearly demonstrated - their active agents may be used to standardize them; and (iii) herbal drugs with uncertain efficacies, but a long history of traditional usage - such drugs can be used for treating common disorders, but should be used exactly as in the traditional practice.
| Approval|| |
The trial can only be initiated when the respective national regulatory authority is satisfied with the quality of data provided on: (i) The safety and efficacy of the drug; (ii) the necessity for the trial; (iii) how the trial is to be carried out - that is: A detailed study protocol; and (iv) the capability of investigators/sponsor. The list of clinical trials conducted on some of the herbals drugs is summarized in [Table 2].
| Conclusion|| |
In this scenario, where the traditional medicine and knowledge is in the verge on getting extinct, it calls for a need to act firmly, and rigorously t protect and preserve our heritage. It is now laid in the shoulders of the regulatory bodies to monitor controlled and quality flow of herbal products and to facilitate their development to clinical trial stages. The goal would not be far away if the regulatory authorities work closely with the academic institutions, research institutes, research clinics and centers, hospitals, industry, and pharmacy faculties.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]
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