Pharmacovigilance of herbal medicines

1 Introduction

Pharmacovigilance is a crucial tool for developing reliable data on the safety of marketed drugs under the practical conditions of clinical usage in society. The aim is to prolong safety monitoring and detect drug adverse events that have been previously unrecognised, despite evaluation in clinical trials. Although these approaches were established for monitoring pharmaceutical medicines, they are also used for assessments of the safety of other medicinal products including herbals, blood products, vaccines and medical devices [1].

The World Health Organisation (WHO) recognised the arising importance of the consumption of herbal medicines worldwide and developed guidelines for the monitoring of herbal safety within the current pharmacovigilance framework – “WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems” [2].

The significance of herbal medicine practices is confirmed by the fact that 67.6% of the population of United States had used herbal medicines – US$ 17 billion were spent by more than 158 million Americans in 2000 [3]. Statistics on 3027 South Australians, predicted that approximately 52.1% had declared at least one form of herbal product in the year 2000 and 23.3% of all respondents had visited at least one herbal practitioner during that year. 57.2% of herbal users did not discuss it with their physician [4]. A recent report from Germany indicated that more than 70% of the population used “alternative medicines” and for majority, herbal medicinal products were the first choice in the treatment of minor diseases or disorders. About 80% of the developing world’s population depends on traditional medicine for their primary healthcare [3]. Results obtained from studies in Nigeria show inadequate adverse effects monitoring amongst the practitioners and underscore the necessity to educate and enlighten herbal medicine practitioners on the need for pharmacovigilance activity of herbal products [5].

Prognoses for next years for the global herbal market are promising. New reports estimate to reach about US$100 billion by 2015 [6], and US$107 billion by 2017 [7]. One possible reason could be related to the growing aging population. A group of the first Baby Boomers are turning 65 this year and they are a major consumer group of herbal drugs and supplements, particularly women in the middle-age. Negative opinions about herbal ingredients (such as ephedra) have been reduced. The reports note a “major tendency” in the herbal market as the shift from single ingredient preparations to the largest segment “multiple ingredient-based medications” is constantly rising – 20% of adult patients are using a dietary supplement with at least one herbal ingredient [8]. The market for homeopathic and herbal remedies continues to grow, and it was estimated to increase 2.6% from 2011–12. According to reports from Global Industry Analysts, Europe is the primary herbal market that shares 45% of total, next is North America with 11% , Japan 16% , ASEAN countries 19% and the remaining with 4.1% . Market with the highest growth rate is Asia-Pacific with CAGR (Compound Annual Growth Rate) of 10.7% through 2015 [6]. Countries like Japan and China have successfully marketed their traditional medicines abroad. Sales of herbal dietary supplements in the United States increased by 7.9% in 2013, reaching a total estimated figure of six billion dollars for the first time. The total sales figure of US$994,228,073 for botanical dietary supplements in 2013 is the reflex of an increase of 9.4% compared to 2012 [9]. The systematic evaluation of safety and efficacy of herbal products and preparations is thus of vital importance from both medicinal and economic perspectives [8].

About two centuries ago, health care system was dominated by natural materials derived from plants, animals and minerals. The medicine traditions were developed over generations and had been mostly transmitted orally by local herbal medicine practitioners. Numerous aspects of Ethnomedicine systems from many cultures – Ayurveda, Siddha and Unani medicine from the Middle East and South Asia, Kampo medicine from Japan, Traditional Chinese Medicine (TCM), Muti from Southern Africa, Ifá from West Africa, Islamic medicine – have been well documented and could be an enormous potential for the development of novel agents.

The end of World War II initiated the rapid development of advanced chemical technologies. Majority of natural products declined its use in the West when more predictable synthetic drugs were made commonly available. However, about 25% of drugs currently used [10], owe their active properties to plants as isolates or modified isolates, like it was with aspirin, as synthetic compounds. Atropa belladonna, Papaver somniferum, Digitalis purpurea and Hypericumperforatum are examples of plants that have strong position in present treatments.

Since around 30 years, popularity of herbs and traditional medicine is again increasing steadily. Supportive was a fact, that many medicinal herbs started being sold in drug-like forms such as capsules, tablets, covered-tablets, and pastilles, which may be more attractive or tasty for consumers. These concentrated formulations made application easier to dose regularly in high concentrations.

It is estimated that 40,000–70,000 plant species are used currently as medicines [10]. The World Health Organization (WHO) admitted the widely usage of plants in the early 1970s and started supporting governments to effectively use local knowledge of herbal medicines for disease prevention and health campaign. However, herbal medicines have many weaknesses. These include insufficient and unacceptable requirements for safety, efficacy, standardization, and inconsistent production practices. In the Ipsos MORI report [11] published in November 2008, 77% of British adults agreed with support and need for regulation of herbal medicines.

Modern medicines are relatively more focused on particular diseases, based on specific etiopathological entities. Many of current plaguing humanity diseases are multifactorial, e.g. cancer, so the rational becomes the research of multi-target drugs. Screening of medicinal plants as a source of antitumor agents started in the middle of last century, with the isolation of vinca alkaloids-vinblastine and vincristine. More than 60% of cancer therapeutics registered on the market or under testing is based on natural products [12, 13].

The choice of the patient to use drugs with plant origin may be caused by several factors, involving poor accessibility to modern drugs, high costs, shortage of physicians, over the counter availability, opinion that natural is absolutely safe, more a adverse effects reported with modern medicine than for herbal preparation, placebo effect, cultural and religious beliefs, educational level, lack of effective treatments, peer influence, etc. Obstacles to use of herbal medicines may be: potential for interactions, difficulties to identify ingredients, less knowledge of adverse reactions of herbal drugs and lack of good manufacture practices.

Traditional medical knowledge, often called complementary or alternative medicine, has two potential values – one as an easy accessible and low-cost source of medicines for primary health care and other as the source for finding novel leads and/or targets for drug development.

2 Standardization as a crucial component of quality control

All medicines, synthetic or of plant origin, should fulfil the basic requirements of safety, quality and efficacy. With the increasing commercialization of traditional medicine, quality control of herbal products is of paramount importance. Herbal substances, preparations and herbal medicinal products are evaluated by the quality of the raw material, development, in-process controls, manufacture controls, and validation applied to them throughout all process. Standardization of herbal multifarious preparations is a highly difficult subject. Inadequate standardization and lack of quality specifications is the most often criticized aspect of herbal medicines [14, 15].

The raw plant material quality is affected by some factors such as geographical origin, genotype, parts of the plant used, collecting period, hygiene conditions, storage, processing, extraction, proportions of herbs and/or processing of the combined herbs as medicines. Therefore, the standardization of the raw plant material is mandatory to establish the quality of herb-drug product. Cultivation, collection and harvesting of medicinal plants should follow appropriate guidance such as the “WHO Guideline on good agricultural and collection practices for medicinal plants” [16] or “Agricultural and Collection Practice for starting materials of Herbal Origin in European Union” [17].

In 1998, in response to the growing interest of medicinal plants, WHO published “Quality control methods for medicinal plant materials” [18] – test procedures for assessing raw plant materials. Another essential guidance is “WHO guidelines on good manufacturing practices (GMP) for herbal medicines” [19] which advices and launches rules for quality control of finished herbal products.

Monitoring requirements for the quality of herbal products may change depending on the country. The European Medicines Agency (EMA) provides secretary support to the Committee on Herbal Medicinal Products (HMPC), which is responsible for compiling and assessing scientific data on herbal constituents and combinations, with a focus on safety and efficacy. According to Directive 2004/24 EC [20], herbal medicines with traditional use that are acceptably safe, but without proofs of efficacy, could be classified as “traditional herbal medicine product” (THMP).

New European regulations, which initiated on May 2011, require herbal products to be licensed-Marketing Authorisation Holder (MAH) - with the need to submit the adequate proposal to the Regulatory Authority. In order for a medicinal product, or its corresponding products, to be classified as THMP, it must have been in medicinal use for a period of at least 30 years (more than 15 years must be related to the EU). After May 1, 2011 all unlicensed herbal products had to be registered as medicines or they would disappear from the market (they could be also labelled as food supplements).

The procedures and techniques used in the manufacture and quality control of herbal medicines were often substantially different from those employed for conventional pharmaceutical products. Good manufacture practices (GMP) in production are essential to guarantee the quality, safety and efficacy of composite products of biological origin such as herbal medicines. All steps: selection, sampling, testing of plant material, stability studies, packaging and labelling must be under monitoring.

3 Safety as a fundamental principle

Resolution WHA23.13 on international monitoring of adverse reactions to drugs [21] from 1970 was a result of cooperative work between The WHO Collaborating Centre in Sweden and the Uppsala Monitoring Centre (UMC), within International Drug Monitoring Program, and it was the first harmonized program of pharmacovigilance.

Quantitatively assess is mandatory to conflicting clinical data and the verification of herbal materials is also needed. Pharmaceutical corporations, drug regulators, health care specialists and also patients need to understand the potential risks of these medicines and their responsibility in minimising and managing those risks.

In EU, each application for authorisation of a medicinal product must be prepared by the Marketing Authorisations Holders (MAH). Documents required are referred in Directive 2001/83/EC [22]; details on the documentation needed for traditional herbal medicinal products (THMP) are mentioned in article 16c. Bibliographic review of safety data (non-clinical overview), expert report and additional data, if needed, are obligatory. HMPC provides a guidance method [23] to present the information and the dossier needed for an application [24].

The variety of herbal products is a challenge for herbal pharmacovigilance. Patients should be educated and encouraged to inform physicians, nurses and pharmacists about used therapies, which could bring appropriate data about side effects, interactions and efficacy. Data of herbal medicines are available in several databases specialized in this area. The EMA launched the platform EudraVigilance in 2001, which is an information system planned to manage information on safety reports, with help of the International Conference on Harmonisation (ICH). Collected data are being published in the European database of suspected adverse drug reaction reports – www.adrreports.eu. CHMP (The Committee for Medicinal Products for Human Use), PRAC (Pharmacovigilance Risk Assessment Committee) together with Member States and MAHs, manage safety signals of new or known adverse events, from sources such as spontaneous reports, clinical studies and scientific publications. The valuation of safety signals is part of standard pharmacovigilance. Crucial is ensuring that regulatory authorities have the most up-to-date information on a medicine’s benefits and risks. Suspected Unexpected Serious Adverse Reactions (SUSARs) reports occurring during clinical trials are reported electronically. No existing mechanisms to gather and organize data from traditional practitioners about the plants, processing, formulation methods used in treatments, efficacy, or adverse reactions, made ethnic knowledge systems oftenunreachable.

Inconvenient is a fact that regulatory requirements for the quality of herbal products vary between geographic zones. The same herbal product can be authorized as a drug in EU or as a dietary supplement in the US. A giant problem is Internet sales, often offering adulterated or not standardized products. The society’s opinion that herbal and natural products are harmless than synthetic drugs can be determined only by the imposition of regulatory standards for these products to be manufactured using these Good Practices.

Some aspects of drug safety, however, are not completely given by clinical trial protocols. Complete evaluation of safety also requires non-clinical assays, such as long-term carcinogenicity and reproductive toxicity studies (teratogenic potential), among others. According to non-clinical safety requirements for any herbal drugs, some crucial changes are desired, like a complete battery of in vitro and in vivo (rodent) genotoxicity assays. For example, data obtained about pulegone [25], a common essential oil, suggests that some traditionally used plants may possess carcinogenic activity and it is needed to eliminate that risk. Seems to have sense, that for herbal medicines, which are indicate for more than 3 or 6 months, long-term rodent carcinogenicity assays (separate or combined to chronic toxicity studies) should be required, and for potentially used by women in reproduction stage, reproductive and developmental toxicity studies should be obligatory. Studies of inhibition/activation influence to liver enzymes, mainly to P480 should be also considered, to predict and avoid potential biotransformation interactions. Knowledge of potential risk of hepatotoxicity, nephrotoxicity, neurootoxicity and cardiotoxicity may be also essential. Important is the development of post risk-management plans for the herbal drug, with collaboration of the regional toxicology and veterinary institutions, pharmacognosy and botany departments of universities, and botanical gardens. Methods used for post marketing monitoring of drug safety should include spontaneous reporting and prescription event monitoring (Fig. 1).

4 Adverse reactions of herbal drugs

As the usage of herbal medicines increased in last decades, reports of suspected toxicity and adverse events were also described. A meta-analysis of 69 prospective and retrospective studies from various regions of the world involving 419 000 patients found that approximately 6.7% of all hospitalisations were as a result of ADRs. More than half of the ADRs that occurred could be avoid by improved procedures according to the treatment (prescriptions, monitoring reactions etc.). 27.6% of adverse events were considered preventable and 38% of them were serious, life-threating or fatal [26].

As a good example of harmonisation, UMC takes ADR reports from over 100 countries around the world and in 2010 their database contained over 4 million reports, of which approx. 21,000 included herbal or natural products [27]. It is evident that ADRs have become a major global public health problem.

Adverse reactions can be owed to:

(i)

side effects (usually detectable by pharmacodynamics and often predictable); e.g. feverfew possess documented side-effects, such as mouth ulcers and swollen tongue [28].

(ii)

reactions occurring as a consequence of tolerance, overdose, overduration, dependence-addiction (detectable either by pharmacodynamics or pharmacovigilance) e.g. overdose of Ginkobiloba can cause some minor side effects such as stomach upset, headache, dizziness, constipation and forceful heartbeat [29], combination with antiplatelet or anticoagulants showed insignificant correlation to the risk of haemorrhage [30]

(iii)

hypersensitivity, allergic and idiosyncratic reactions. e. g. hypersensitivity reactions have been reported for chamomile and other plants from the same Compositae family (Asteraceae) [29].

(iv)

mid-term and long-term toxic effects including liver, renal, cardiac and neurotoxicity also genotoxicity and teratogenicity (detectable by in vitro and in vivo toxicological studies or by pharmacovigilance) [31, 32].

5 Herbal use in specific population groups

Many cultures have developed their own health systems, which were transformed over the centuries by specific for them factors. There are obvious differences in forms of health systems in particular society groups. Epidemiological practice and results of epidemiological analysis make a significant contribution to emerging population-based health management frameworks. Certain groups of patients are characterized by greater usage of herbal medicines and supplements, and differences in reactions may also occur.

6 Conclusion

The healthcare costs are increasing at an alarming rate. The World Bank estimated that trade in raw plant materials and herbal drugs is growing at an annual rate of 5–15% [52]. The “pharmacovigilance of tomorrow” is rapidly recognizing the risk in certain patient groups, improving safety with simultaneous increasing the efficacy at the national and global level. A testing scheme of the efficacy and safety of herbal drugs is presented in Figure 2.

Some of risk factors can be avoided by following standard guidelines for producing herbal medicinal products from herbal or natural sources. The national health authorities should give greater attention to consumer education and qualified practice in provision of herbal medicines. A demonstration of the safety of herbal medicines for registration purposes should include at least in vitro and in vivo genotoxicity assays, long-term rodent carcinogenicity tests (for drugs intended to be continuously used for >3 months or intermittently for >6 months), reproductive and developmental toxicity studies (for drugs used by women of reproductive age) and examination of the effects on drug-metabolizing enzymes.

7 Conflict of interest

The authors declare that they have no competing interests.