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Vigilance of Natural Health Products

Mano Murty, MD, CCFP, FCFP,* Kevin Bernardo, ND, BHsc,* and Alison Ingham, PhD**

*Marketed Health Products Directorate, Health Canada

(contact: mano_murty@hc-sc.gc.ca)

**Natural Health Products Directorate, Health Canada

This chapter is an introduction to the science of natural health products (NHPs) and related vigilance activities. For simplicity, the term natural health products (NHP) will be used to denote a wide variety of substances, as defined in Canada’s regulatory definition (see Table 51.1).

Studies show that the use of NHPs is increasing in the general population, including among children, pregnant women, and seniors. The perception is that “natural” means safe and, therefore, not able to cause adverse reactions (ARs) (Brulotte and Vohra 2008; Chiu et al. 2009; Ernst 1999; Forster et al. 2006; Kelly et al. 2005; Vohra et al. 2009; Woodward 2005). These products are being used to maintain health and to prevent and treat various medical conditions. Although most NHPs are considered low-risk, serious ARs associated with NHPs continue to be reported (Furbee et al. 2006). An element related to safety is direct-to-consumer advertising, which may lead to misuse by consumers, some of whom may have chronic or serious illness, increasing the risk of adverse interaction (Torok and Murray 2008). Self-diagnosing an ailment and self-selecting a treatment can lead to serious ARs, masking a serious illness or causing a delay in receiving necessary treatment (Lapi et al. 2008).

Table 51.1		Health Canada’s Definition of a Natural Health Product
Substance		Plants, algae, bacteria, fungi, nonhuman animal materials
		Extracts or isolates of the above
		Vitamins and minerals
		Amino acids and essential fatty acids
		Synthetic duplicates of natural ingredients
		Probiotics
		Traditional and homeopathic medicines
Function		Diagnosis, treatment, mitigation, and prevention of disease
		Restoring or correcting organic function to maintain and promote health

Source: Health Canada Website. Overview of natural health products regulations. http://www.hc-sc.gc.ca/dhp-mps/prodnatur/legislation/docs/regula-regle_overapercu-eng.php. Accessed September 1, 2010

Labeling is another concern because it may or may not reflect actual product ingredients and indications for appropriate use. While Canada has implemented labeling standards of authorized NHPs, many unauthorized NHPs available worldwide have minimal or misleading labels (Web Resource 51-1).

These and other emerging safety issues have raised awareness within the scientific and medical communities about including NHPs in the pharmacovigilance framework.

As many of the NHPs on the international market do not undergo premarket studies, safety data are sparse. This is the main challenge not only to the regulators but also to all relevant stakeholders, such as healthcare practitioners, consumers, and the NHP industry (Murty 2007).

Special considerations and expertise are required to collect quality data, identify and assess signals, and implement risk mitigation strategies with NHPs. A dedicated vigilance program for NHPs is imperative for promoting public safety. Such a program will need to consider some of the following key factors: (a) prevalence of NHP use and safety issues; (b) data sources and Adverse Reaction Reporting (ARR); (c) ARs and causality assessment; (d) safety analysis: signal evaluation; (e) NHP interactions and medical relevance; (f) international collaboration: methods to address regulatory diversity; (g) initiatives to strengthen vigilance of NHPs. This chapter will give an overview of these factors and associated challenges. The Canadian Regulatory framework for NHPs will be used to exemplify some methods to strengthen vigilance of NHPs.

Canada and the United States report more than 70% of their population use NHPs (IPSOS Reid 2005; Loman 2003). Use by children in some countries has been estimated to be 17–33% (Brulotte and Vohra 2008). NHPs are readily available without prescription in grocery stores, retail pharmacies, health food stores, and on the internet. It is now well known that NHPs can exhibit pharmacological and physiological activities and, in some cases, can cause harm (McFarlin et al. 1999; Menniti-Ippolito et al. 2008). As the use of botanical medicines increases, consumers expose themselves to potential ARs, many of which go undetected, as a medical consultation is not always sought. Interactions between NHP–drugs, NHP–NHPs, and NHP–food leading to clinically relevant events have been reported (De Smet 2006; MacDonald et al. 2009). These form some of the safety issues that need to be considered when reviewing these products.

Even when safety studies are available on individual ingredients, the multitude of ingredients used in combination are poorly studied, and risk cannot be excluded. As accurate data on exposure to NHPs and their consumption are often unknown, estimating a safety issue and the affected population remains a challenge. Lack of guidelines and international regulation of the NHP ingredients and the limited number of human clinical studies on safety and efficacy are some additional factors contributing to potential health risk (Foster et al. 2005).

The role of healthcare practitioners (HCPs) in the overall vigilance of NHPs is critical in obtaining quality data. They are in a unique position to promote disclosure of NHP use and potential ARs at the time of every patient encounter. The reliability of the information connected to the NHP (e.g., quality of the product and assurance of the correct species and part of the plant), is pivotal in evaluating ARs associated with the use of NHPs (Farah et al. 2006). Most NHPs consist of multiple ingredients, the identification of which may be difficult. Safety and efficacy of NHPs depend on the quality of source materials used in production. Several factors determine the quality of source material, including environmental conditions, cultivation, harvesting, collection, transport, and storage. Adulteration of NHPs with pharmaceutical drugs or with other NHP ingredients is a major issue associated with safety and pharmacovigilance of NHPs (Mahady et al. 2008). Another concern with all health products, including NHPs, is counterfeiting. The risk with counterfeit products is that they may not contain the active ingredients that consumers would normally expect in authorized health products

Most countries regulate NHPs as foods or dietary supplements, which are not monitored through AR reporting systems. In Canada, NHPs are regulated according to the NHP Regulations, which allow voluntary, spontaneous ARs to be collected by Health Canada. However, such systems have limitations, such as underreporting and poor quality data. Underreporting is common for all health products; it is estimated to be 10% for pharmaceuticals and <1% for NHPs (Woo 2007).

Some factors that contribute to underreporting include consumers’ and HCPs’ lack of awareness that ARs can be associated with NHPs. Furthermore, many NHPs are regulated in a manner that does not facilitate AR reporting. In addition, many consumers are unaware that they can report ARs. Clinicians often do not have access to toxicity profiles of many NHPs; therefore, they are challenged in recognizing the link to the NHP and reporting the AR.

ARs are considered suspicions, and causality must be verified, which is challenging for many NHPs. Key issues in evaluating adverse events in a spontaneous reporting system include limited medical information, limited manufacturer information, limited ability to analyze trends, and lack of premarket safety and effectiveness information. ARs can be Type A or Type B (WHO 2004). Type A reactions are mostly pharmacological and dose-related, with predictable toxicity (e.g., aristolochic acid-induced nephrotoxicity; St. John’s wort (Hypericum perforatum) altering therapeutic levels of multiple drugs). Type B refers to idiosyncratic reactions (not dose-related, not predictable), such as allergy/hepatitis and anaphylaxis. From our experience, most of the ARs associated with NHPs relate to idiosyncratic reactions (Type B) unless there is an ingredient that has been demonstrated to have inherent toxicity (Vivekanand 2010; Wai et al. 2007).

Acute ARs associated with NHPs are easily detected but may not be immediately attributed to the NHP. However, subtle symptoms of toxicity or long-term detrimental effects, such as carcinogenic, mutagenic, or teratogenic effects, may be easily missed (Singhuber et al. 2009). ARs associated with NHPs relate to multiple factors, such as product pharmacological activity/misidentification or adulteration, consumer use, or interaction with drugs, foods, or other NHPs (see Table 51.2).

Interaction with pharmaceuticals becomes critical if the pharmaceutical, such as warfarin, has a narrow therapeutic index. ARs can be misinterpreted and attributed to a conventional drug or to the disease process. This can lead to inappropriate or delayed management. Causal relationships can be evaluated using several algorithms (Jordan et al. 2010; Naranjo et al. 1981). However, there are challenges and limitations with these tools, as they were mostly designed for single-ingredient products.

The following criteria aid in the causality evaluation of an AR case report: (a) core information (reporter, patient, suspect product, and AR) along with additional information; (b) medical information (age, gender, history, diagnosis, dose, and duration of use, time between product administration and adverse reaction, dechallenge/rechallenge information, concomitant medical conditions and health products, lab analysis, social history, medical intervention); (c) product information (label contents, brand name and ingredient, type of extract, concentration, lot number, expiration date); and (d) Market Authorization Holder (MAH) info (contact name/address). A single botanical may contain multiple constituents, and a botanical combination product may contain several times that number. Variability in active ingredients, some with possible inherent toxicity, and the vast number of ingredients included in some products, limit the ability to assess or attribute to a single NHP ingredient the cause of the AR.

Note: NHP, natural health products.

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