Anushka Mootoosamy and M. Fawzi Mahomoodally*
Introduction
According to the World Health Organisation (WHO), traditional medicine is defi ned as the sum total of the knowledge, skill and practices based on the theories, beliefs, and experiences indigenous to diverse cultures used in the maintenance of health as well as in the prevention, diagnosis, improvement or treatment of physical and mental ailment (WHO 2013). Approximately, 4000 million people in developing countries have recourse to traditional medicine including phytotherapy (use of plants) and zootherapy (use of animals) on a regular basis (Alzweiri et al. 2011). One reason for this is the fact that despite accessibility of allopathic medicine in these countries, herbal remedies have retained their supremacy, owing to the belief of their long-standing use and less side effects (Alzweiri et al. 2011). Recently, the world has witnessed renewed interest in herbal remedies in both developed and developing countries for the management and/
or treatment of various diseases. It is generally argued that herbal remedies are relatively inexpensive when compared to prescription medications and they may be viewed as cost-effective alternatives to conventional pharmaceutical therapies. Moreover, since they are derived directly from nature they are assumed to be safe. They are also free from the negative stigma attached to many commonly prescribed conventional medicines (Ashar and Dobs 2004). There is a great possibility that medicinal plants may turn out to be much more signifi cant sources of bioactive molecules that has ever been imagined for the development of novel pharmaceuticals (Bougel 2007). Currently, much research is being geared towards phytochemicals owing to their modulation ability towards non-communicable diseases like cancer, cardiovascular diseases, diabetes, arthritis, neurodegenerative diseases, and cataract as well as against other infectious diseases amongst others. The underlying reason that has contributed to the reemergence of interest in bioactive phytochemicals is scientifi c proof acquired from well-designed epidemiological,
Department of Health Sciences, Faculty of Science, University of Mauritius, Réduit, Mauritius.
* Corresponding author: f.mahomoodally@uom.ac.mu
toxicological and experimental studies conducted during the previous two decades. Investigations that are being carried out on plants are mostly focused towards their prophylactic approach such as antioxidant properties due to their rich fl avonoids content, which is responsible for their free radical scavenging properties (Srivastava and Vankar 2012).
Furthermore, based on the current growth rate, it is anticipated that by the year 2020, the world population will reach 11.5 billion. The drastic increase in population, insuffi cient supply of quality drugs in certain regions of the globe, unaffordable cost of treatment for common diseases, serious adverse effects of numerous modern conventional drugs presently in use and above all the development of resistance to currently used drugs for infectious diseases have inevitably shifted our attention towards the use of phytotherapy against the management and/or treatment of a multitude of ailments (DMAPR 2012).
Medicinal plants have greatly contributed to the management and/or treatment of diseases for instance HIV/AIDS, malaria, diabetes, sickle-cell anemia and mental disorders (Elujoba et al. 2005). Moreover, Illicium verum (Star anise) which serves as the industrial source of shikimic acid, a principal ingredient used to produce the antiviral drug, Tamifl u (oseltamivir phosphate) which is so far, the only existing drug that may diminish the severity of bird fl u (Wang et al. 2011). Studies carried out have documented the therapeutic effect of many medicinal plants that are utilized worldwide for their therapeutic properties and hence it is undeniable that the knowledge of medicinal plants that the indigenous populations possess is a starting point for modern science to discover new drugs (Clark 2012).
Natural products play a fundamental role in pharmaceutical biology and drug development. According to Joseph et al. (2010) many drugs which are on the market either mimic naturally occurring bioactive molecules or have structures that are fully or partly derived from natural motifs. Medicinal plants continue to contribute signifi cantly to modern prescription drugs by providing novel lead compounds upon which the synthesis of new drugs can be made. According to Newman et al. (2003), 60% of anticancer drugs and 75% of anti-infectious disease drugs approved from 1981–2002, were of natural origins. Moreover, 61% of all novel chemical entities introduced worldwide as drugs during the same period were inspired by natural products. The use of, and search for drugs and dietary supplements derived from plants have increased exponentially during the recent years. Pharmacologists, microbiologists, biochemists, botanists, and natural-products chemists all over the world are currently investigating medicinal herbs for phytochemicals and lead compounds that could be developed for treatment of various diseases (Acharya and Shrivastava 2008). After decades of serious obsession with the modern medicinal system, people are now looking at the ancient healing systems like Ayurveda, Siddha, Unani and Chinese traditional medicines with the view of treating diverse types of ailments. The main reason for this shift is the adverse effects associated with synthetic drugs and their narrow therapeutic window and index (Bigoniya et al. 2011).
According to the Dietary Supplements Health and Education Act (DSHEA) of 1994, premarket testing of herbal products to determine their safety and effi cacy was no longer required. Supplements were assumed to be safe unless proven otherwise by the Food and Drug Administration (FDA). This has resulted in a plethora of herbal products fl ooding neighborhood supermarkets and drugstores. The lack of regulation of herbal supplements is problematic due to various reasons. Firstly, no universal standards are in place to guarantee homogeneity among different herbal products. Secondly, there is also no quality assurance that the active ingredient from the plant is present and variations exist between batches from the same manufacturer due to differences in plant composition, handling and preparation. Another issue is that in many cases the active ingredient(s) is unknown, thus making standardization and identifi cation impossible (Ashar and Dobs 2004).
It is also a known fact that not all plants are the same or even members of the same species. While some are safe and effective for specifi c diseases and purposes, others are not. The general perception that herbal remedies are very safe and devoid from side effects is not true and should not be taken for granted.
Plants can produce undesirable side effects which can be lethal. A particular plant part will possess an array of active constituents and some of them may be toxic (Wickramasinghe 2006). Moreover, the risks of herb-drug interactions cannot be overlooked or ignored. Hence, the pressing need of conducting clinical trials to allow safety and effi cacy data to be amassed for herbal products are becoming a basic need for both the scientifi c community and consumers.
By defi nition, clinical trial is a systematic study of medicine in human subjects including patients or healthy volunteers, intended to validate or reveal their action, adverse reaction, and/or absorption, distribution, metabolism, and excretion, and to identify their effi cacy and safety (ICH 1997, Yuan et al. 2011, www.ich.org). It is generally agreed that traditional medicinal products should be subjected to more clinical research as this would help to select products of interest for further investigations in ethnopharmacology and it could also provide immediate recommendations for the population using the assessed local treatments (Graz et al. 2007). Clinical trial is also argued to be more important than preclinical experimental investigations to evaluate effi cacy and safety of both modern and traditional herbal medicines.
This is because the bioactivity, pharmacodynamic and toxic results obtained from in vitro bioassays and in vivo animal studies might differ signifi cantly from the effi cacy and toxicity on human bodies, due to absorption, metabolism and species differences between animals and human beings (Yuan et al. 2011).
This chapter reviews the various ways in which clinical studies of traditional herbal medicine can be performed, summarizes data generated from key clinical trials conducted to determine safety and effi cacy of herbal products and ends by highlighting key challenges of clinical studies on herbal medicine which need to be addressed.
Clinical trial design for traditional medicine
Clinical studies of traditional medicine, allows for screening plants with higher chances to yield novel drug candidates and may also result in information of immediate interest for patients and practitioners who make use of the traditional formulations, particularly in relation to their effi cacy, toxicity and also dosage (Teixeira and Fuchs 2006). A clinical trial design is defi ned as a scientifi c, thoughtful and detailed plan which must be established prior to any stage(s) of clinical trial, so as to enable the trials to run smoothly and to obtain accurate and reliable results (ICH 1997, Yuan et al. 2011, www.ich.org). The main purposes of clinical trials for herbal medicine are to scientifi cally validate the therapeutic effects, safety and effi cacy of herbal medicine even though many of them have been used since time immemorial and to elucidate its possible adverse effects and toxic reactions (Yuan et al. 2011). Diallo et al. (2006) and Graz et al. (1999) reported that clinical studies of traditionally used medicinal plants can be conducted at relatively low cost, when the study is conducted in a setting where the treatment of interest is commonly used and has a known safety profi le. If the herbal product is a commonly used medicinal plant (e.g., medicinal food plant or spice) then the clinical trial should be set up based on data obtained from common users of the medicinal plant. In order to avoid variations in the outcomes of a clinical trial with an herbal product, a number of questions and challenges as elaborated by Yuan et al. (2011) should be taken into consideration as depicted in Table 5.1.
Toxicological studies prior to clinical studies
Clinical trials of traditional medicine are made easier than the usual clinical trials because a good documentation of traditional use alleviates the constitution of the toxicology/safety fi le, so long as the clinical study is conducted with the traditional medicine being prepared and applied according to the selected local customary recipe (WHO 2000). Information about known side effects of medicinal plants can pave the way for further research on its toxicity. According to Graz et al. (2007), proponents of toxicology studies argue that long-used products may have an unknown long-term toxicity. On the other hand, opponents refute that what we commonly eat are generally accepted as safe despite a lack of formal in vitro or in vivo toxicology studies hence common traditional treatments should be regarded in the same way. Nonetheless, before proposing a clinical study feasible, potential confl icts on the necessity of preliminary toxicology studies (in vitro or in vivo) must be addressed and resolved, with a special emphasis on long term use and reproductive toxicity. When conducting clinical trial of an herbal remedy, information on medicinal plant collection (taxonomy), preparation, dose, and frequency of administration are fundamental to reduce the occurrence of toxicity and future serious adverse effects.
Randomized controlled trial
According to the FDA (2004), clinical trial for herbal remedy can directly start on phase III. Phase III clinical trial is designed to confi rm the safety and therapeutic effi cacy of an herbal medicine as it is used traditionally. Hence, a clinical trial of herbal medicine or product is mostly randomized, double-blind, and a placebo-controlled trial.
Randomized controlled trials are research studies that aim to evaluate the effi cacy and toxicity of a drug treatment (Saturni et al. 2014). In randomized controlled trials, each subject is randomly allocated to receive the herbal product or the placebo. Randomly assigning a single subject into a treatment or control group will ensure that the populations are similar in both groups (Yuan et al. 2011). Moreover, random assignment to treatment groups minimizes bias (Jaillon 2007). There are various ways to achieve randomization, for instance lot drawing, checking random digital tables or random arrangement tables amongst others (Yuan et al. 2011). Blinding is utilized in clinical trial to reduce biases resulting from management, treatment, assessment, or interpretation of results from subjects or researchers knowing the assigned treatment, thus ensuring that the outcomes are not affected by knowledge of treatment assigned.
In a single—blind trial, only the subjects are not aware whether they receive test treatment or a placebo whereas in double-blind trial, neither the subjects nor the researchers know which subject is given the treatment or a placebo. During phase III clinical trial, routine examination of the subjects should be carried out using a fi xed schedule and time of administration of the herbal medicine should be well established and documented. Proper training should be given to personnel to ensure smooth running of the clinical trial as per international guidelines and to prevent mistakes (ICH 1997, Yuan et al. 2011, www.ich.org).
Clinical trial protocol
A clinical trial protocol is a document that describes the aim(s) and objective(s), scientifi c motivation, treatment procedure (dosage, course, and measurement), study population, control group, statistical analysis and organization of a clinical trial. It should also provide details on the composition of the research team (ICH 1997, Yuan et al. 2011, www.ich.org). Graz et al. (2007) have suggested that when planning a clinical study on a traditional medicine, it is very important to have an interdisciplinary research group, with the collaboration of traditional practitioner/healers, ethical investigators, skilled clinicians, botanists/pharmacists, epidemiologists/statisticians and patients. Sharing questions regarding the design of research protocols and the interpretation of the results can help save much time and may avoid signifi cant mistakes and bias. It has also been proposed that it is fundamental to provide an exact template for trial Table 5.1. Major questions and challenges to be taken into consideration (Yuan et al. 2011).
Questions and challenges which need to be addressed
Which species of plant or which taxonomic group does the plant material belong?
In which region or season of the year should the plant be collected?
Will the herbal product be administered (e.g., dosage, forms) the same way as it is used traditionally?
Which population will be targeted as study subjects?
How will the participants be allotted into the experimental or control group?
Participants belonging to which age group will be selected?
Which sample size will be best suited to be used in this study?
Which allopathic drug (or will it be another known herbal product) will be used to make comparison or use of pla- cebo?
In case a placebo is being used, will it be able to mimic the strong aroma and taste of the herbal remedy?
How will the effectiveness of herbal product be determined over time?
Do you have a clear knowledge on the onset time and natural course of the ailment treated and/or managed with the herbal product?
Any method or tools available to determine pharmacokinetic and pharmacodynamic data?
implementations so that all investigators involved perform the clinical trial in exactly the same way (Yuan et al. 2011). As in any conventional clinical trial, the clinical trial protocol should be ready before the start of the clinical trial and should satisfy any administrative and legal criteria set by the health authorities in the country in question. The relevance of the research question, the rigor of the data collection and analysis, and the importance of the observed effects are key factors which make a clinical study valuable and valid (Graz et al. 2007).
Superiority and non-inferiority clinical trials
A clinical study of superiority design is intended to demonstrate that the herbal treatment is more effective than a placebo in a placebo-controlled trial. Nonetheless, sometimes the investigational product, in this case an herbal product or polyherbal formulation is compared to a reference treatment without the objective of showing superiority. These control trials are designed to demonstrate that the effi cacy of the herbal product is not worse than that of the active comparative treatment (for instance a known conventional drug). These trials are termed as non-inferiority clinical trials (Karlberg and Speers 2010).
Sample size
Phase III clinical trial should be conducted with suffi cient number of participants in order to obtain reliable results. Therefore, to ensure that neither too many nor too few subjects are included in the herbal intervention, the sample size should be calculated prior the start of the study. The sample size is defi ned as the total number of subjects participating in a clinical trial. A sample size which is too small will lead to an incorrect conclusion due to statistical bias. On the other hand a sample size which is too large is more expensive and time-consuming to conduct. According to Röhrig et al. (2010), the chances of success in a clinical trial and the quality of the research results depend to a large extent on sample size planning. Sample size planning should always be conducted in collaboration with a biometrician or an expert statistician. The unpaired t-test is often used to determine sample size. Provision should be made to recruit more subjects since drop outs are common in clinical trials and additional subjects need to be added in each group.
Recruitment of subjects
The appropriate subjects can be identifi ed and recruited from a cabinet of physicians, public hospitals and/or private clinics or can also be recruited using newspaper and/or media advertising (www.ich.org).
Participants are selected based on inclusion and exclusion criteria, which are established by investigators of the study. Inclusion criteria are defi ned as characteristics which make prospective subjects eligible to participate in the study while exclusion criteria are characteristics which prevent prospective participants to be part of the study. Inclusion and exclusion criteria include factors for instance age, participant’s ability to give informed consent, type and stage of the disease, participant’s treatment history, whether the participant is pregnant or breast feeding, participant’s agreement to come for follow ups amongst others (ICH 1997, www.ich.org). The informed consent is a legal document which informs prospective participants the nature, aims and objectives, procedures, duration, possible risks and benefi ts of the study before they make their decision whether to participate or not. Participants who agree to participate in the clinical trial should sign the informed consent. They also have the right to withdraw from the clinical trial at any time during the course of the study (Li et al. 2009).
Controls
In many regions of the world, strong belief that herbal medicines will be benefi cial and safe may introduce bias, which can be minimized by careful attention to study design including appropriate control groups (WHO 2005). The establishment of a control group is fundamental for comparison. Control studies are used to determine whether there is a signifi cant statistical difference between the herbal product/formulation
and the positive control in terms of the therapeutic effects. Therapeutic effects through clinical treatment may be achieved by the herbal product or some other factor, for instance psychological effect. Therefore, control studies are adopted to minimize the infl uence of other factors to the utmost degree (Yuan et al.
2011). Figure 5.1 summarizes three types of control groups which can be adopted when conducting clinical trial of traditional medicine.
Controls
Active (positive) control No treatment control
Placebo control
An allopathic medicine with the same effect as the herbal drug is chosen as a standard control for comparison.
Provides more safety information.
Easily performed in clinical trial with a larger sample size
Control group that receives no treatment.
Used in clinical trials for chronic diseases.
Placebo is a substance devoid of therapeutic properties.
It enables researches to isolate the effect of the herbal remedy.
Justifies the therapeutic effect of the herbal drug and evaluate its safety and efficacy.
Dose-response control
Carried out to determine the relationship between dose and efficacy and side effects.
Yields dose-response information
Dose may be fixed or raised gradually
Figure 5.1. Types of control groups (Yuan et al. 2011, ICH 2001).
Cross-over trials
The design of randomized controlled trials consists of patients being randomly placed into two different, parallel treatment groups. However, not all randomized controlled trials are of this design. In contrast, to a parallel group trial, in cross-over trial each subject receives two or more treatments in a random order;
that is the sequence of treatment which is randomized. For instance, a cross-over trial is conducted to investigate the effect of medicinal plant Y to reduce blood glucose level in diabetic patients. The subjects participating in the trial are assigned a regimen of one week of the medicinal plant Y and one week of a matching placebo in a random order. At the end of each week, blood glucose level is measured to determine effi cacy of the medicinal plant Y. The particular advantage of cross-over trial is that the treatment is evaluated on the same patient, allowing comparison at the individual level rather than at the group level. Since each patient receives both interventions, cross-over trials require half the number of patients to produce the same precision as in parallel group trial. Moreover, variation in repeated responses within the same patient is usually less as compared to different patients. However, the major concern with cross-over trial is the risk of carry-over effect whereby the treatment given in the fi rst period has an effect that persists into the second period (Elbourne et al. 2002).