**5. Regulatory requirements and risks**

The regulatory requirements for different product categories containing natural substances like pharmaceuticals, nutraceuticals, and cosmeceuticals vary from rather stringent to gener‐ ous to non-existent at an International level. To exemplify regulatory approaches for the three aforementioned categories, an overview of the current situation in North America (U.S. and Canada) and the European Union is summarized. In many areas we have presented exact wording from the respective governing websites, as the phrasing of such represents the official context and any deviation thereof could be misleading.

#### **5.1. Natural product-derived pharmaceuticals**

Natural products constitute a key source of pharmacologically active ingredients in a variety of novel agents with therapeutic potential in a wide range of diseases. Pharmaceuticals containing natural products or compounds derived from natural product scaffolds or tem‐ plates have to undergo the same stringent approval process as drugs obtained from purely synthetic origin.

#### *5.1.1. North America*

Tissues of marine invertebrates present unique problems for extraction, because of their high water and salt content, and the promising compounds may be present only in low amounts and/or can be very difficult to isolate. Sponges and their microbial fauna are mostly not suitable for culture, and the compounds of interest need to be extracted and purified from specimens collected in the wild [17, 93]. Marine organisms and microbes constitute a valuable potential source of NCEs and structural templates for drug discovery in the future, but may necessitate tons of raw material to isolate milligram to gram amounts of the compound of interest [97]. This difficulty combined with the challenges for synthetic approaches to obtain significant quantities of potential new drug candidates, based on their often highly complex structures, are obstacles that can hamper their use in discovery and development [58, 97]. In some cases, supply issues could be resolved by semi-synthesis or total synthesis of the compound, the development of synthetic analogs with more manageable properties, or by design of a pharmacophore of reduced complexity, which can then be synthesized [17, 92, 97]. Fragments or synthetic analogs with simplified structures may retain bioactivity or even show improved

18 Using Old Solutions to New Problems - Natural Drug Discovery in the 21st Century

Furthermore, environmental aspects can constitute significant hurdles for supplying material for discovery and development as the product may stem from an endangered species or the wild collection of the producing species may be detrimental to its originating terrestrial or marine ecosystem. Additionally, as mentioned above, because of their low abundance many compounds of interest from natural sources need to be extracted and purified from large quantities of specimen collected in the wild, which in turn carries the risks of over-exploitation and habitat destruction [17, 93]. Radjasa *et al.* provide a positive outlook for marine ecosystems and state "*There is optimism for the future because the international marine bioorganic community clearly recognizes that invertebrates must be harvested and studied in an environmentally sustainable manner"* [92]. Although aquaculture of marine species or culture of bacteria seem like logical alternative sources to obtain product, they are not viable avenues in most cases because it proves difficult to impossible to culture the source organisms (especially invertebrates and/or their microbial symbionts like bacteria etc.) or they may not produce the compound of interest under the given culture conditions [12, 17, 95, 97]. Findings indicate, that the bacterial composition on invertebrates is largely independent from sponge taxonomy or locality of collection and the bacteria most likely are contaminants from the ocean water rather than

specific symbionts, which further exacerbates the cultivation problem [97, 108].

Another challenge can result from redundant activity determination in assay systems and the mixed composition of natural product extracts. With over 150,000 known small molecules characterized from natural sources, previously known natural products are often re-isolated in the course of bioassay-guided fractionation [84]. While this may be acceptable if the biological activity is new, it is frustrating to waste resources on the *de novo* structure elucidation of known compounds. Furthermore, not all compounds contained in natural product extracts are drug leads and it is extremely desirable to remove "nuisance compounds" like tannins, phorbol esters, saponins, and anionic polysaccharides; the latter, for instance, being highly

activity towards the target [12].

active in cellular HIV bioassays [35].

#### *5.1.1.1. United States of America (U.S.)*

The U.S. Government Office for the Control of Food and Drug Administration (FDA) oversees the regulatory control of pharmaceuticals including new treatments based on natural products [109]. The FDA's Center for Drug Evaluation and Research (CDER) role is to evaluate and approve new drugs before they can be sold ensuring that drugs are safe and effective for intended use and that their health benefits outweigh their known risks [109].

#### *5.1.1.2. Canada*

In Canada, Health Canada fulfills the same role as the US FDA according to the mandate under the authority of the Food and Drugs Act and the Food and Drug Regulations [110].

#### *5.1.2. European Union*

The European Medicines Agency (EMA) with headquarters in London/England regulates drugs and medicinal products in the European Union (EU) [111]. On April 30th, 2011 the EU entered into force the directive on herbal medicine products called Traditional Herbal Medicinal Products Directive 2004/24/EC, THMPD [111]. The regulation came as a subdirective for the act on Human Medicinal Products Directive 2001/83/EC claiming a unique set of information on a herbal substance or herbal preparation for all EU Member States. Such could be used when evaluating marketing applications for herbal medicinal products from companies and covers medicinal products containing herbal substances/preparations [111]. To reach the market, these must fall within one of the following three categories, as outlined on the EMA website [111]:


In summary, while safety needs to be shown for products, proof of efficacy is not always a requirement and only the traditional indications in specified conditions must be plausible. Nonetheless, and irrespective of the regulatory pathway to access the market, the quality of the herbal medicinal product must always be demonstrated [111].

The Directive provides definitions for herbal medicinal products, herbal preparations and herbal substances, as follows [111]:


substances are precisely defined by the plant part used and the botanical name according to the binomial system (genus, species, variety and author).

**•** *Herbal preparations:* Preparations obtained by subjecting herbal substances to treatments such as extraction, distillation, expression, fractionation, purification, concentration or fermentation. These include comminuted or powdered herbal substances, tinctures, extracts, essential oils, expressed juices and processed exudates

Additionally, it has been noted that from a herbal substance (e.g. valerian root) different herbal preparations (e.g. a valerian root extract using 70% ethanol) can be made; in such cases, both can represent the active ingredient in an individual herbal medicinal product [111].

#### **5.2. Nutraceuticals — Dietary supplements (U.S.)/Natural health products (Canada)**

Even if natural health products (NHPs) or dietary supplements are considered as or expected to be safe, they may still carry potential risks in themselves or through interactions with prescription or Over The Counter (OTC) drugs. This is illustrated by the previously described example of *aristolochic acid*, a powerful nephrotoxin and a human carcinogen associated with chronic kidney disease and upper urinary tract urothelial carcinomas after ingesting *Aristolo‐ chia* herbs in conjunction with a weight-loss regime [80, 81]. Furthermore, interactions between NHPs and prescription medicines are of increasing concern and need to be considered by physicians and patients alike [112]. Mills *et al*, in their evaluation of 47 trials which examined drug interactions with 19 different herbal preparations, observed potentially clinically significant drug interactions with St. Johns Wort, garlic, and American ginseng [113].

#### *5.2.1. North America*

*5.1.2. European Union*

on the EMA website [111]:

bibliographic safety and efficacy data.

herbal substances, as follows [111]:

The European Medicines Agency (EMA) with headquarters in London/England regulates drugs and medicinal products in the European Union (EU) [111]. On April 30th, 2011 the EU entered into force the directive on herbal medicine products called Traditional Herbal Medicinal Products Directive 2004/24/EC, THMPD [111]. The regulation came as a subdirective for the act on Human Medicinal Products Directive 2001/83/EC claiming a unique set of information on a herbal substance or herbal preparation for all EU Member States. Such could be used when evaluating marketing applications for herbal medicinal products from companies and covers medicinal products containing herbal substances/preparations [111]. To reach the market, these must fall within one of the following three categories, as outlined

20 Using Old Solutions to New Problems - Natural Drug Discovery in the 21st Century

**1.** a product can be classified under traditional medicinal use provisions ('traditional use') accepted on the basis of sufficient safety data and plausible efficacy: the product is granted a traditional use registration (simplified registration procedure) by a Member State,

**2.** a product can be classified under well-established medicinal use provisions ('wellestablished use'). This is demonstrated with the provision of scientific literature estab‐ lishing that the active substances of the medicinal products have been in well-established medicinal use within the Union for at least ten years, with recognized efficacy and an acceptable level of safety. As a result the product is granted a marketing authorization usually by a Member State or by the European Medicines Agency. While both classifica‐ tions have specific requirements, both regulatory paths involve the assessment of mostly

**3.** a product can be authorized after evaluation of a marketing authorization application consisting of only safety and efficacy data from the company's own development ('stand alone') or a combination of own studies and bibliographic data ('mixed application'). As a result the product is granted a marketing authorization by a Member State or by the

In summary, while safety needs to be shown for products, proof of efficacy is not always a requirement and only the traditional indications in specified conditions must be plausible. Nonetheless, and irrespective of the regulatory pathway to access the market, the quality of

The Directive provides definitions for herbal medicinal products, herbal preparations and

**•** *Herbal medicinal product:* Any medicinal product, exclusively containing as active ingredients one or more herbal substances or one or more herbal preparations, or one or more such

**•** *Herbal substances:* All mainly whole, fragmented or cut plants, plant parts, algae, fungi, lichen in an unprocessed, usually dried, form, but sometimes fresh. Certain exudates that have not been subjected to a specific treatment are also considered to be herbal substances. Herbal

herbal substances in combination with one or more such herbal preparations.

Agency via the centralized procedure if all requirements are met.

the herbal medicinal product must always be demonstrated [111].

#### *5.2.1.1. United States of America*

In the U.S., biologically active food and dietary supplements are regulated by the FDA and are classified as food and nutrition, not drugs [88]. The FDA website provides a detailed overview of their regulatory approach concerning nutraceuticals. The following paragraphs reflect some core points as outlined on the FDA's respective website [88].


that is the basis on which manufacturers/distributors have concluded that a dietary supplement containing a new dietary ingredient will reasonably be expected to be safe under the conditions of use recommended or suggested in the labeling [87].


#### *5.2.1.2. Canada*

In Canada, the use and sale of natural health products (NHPs) is on the rise [8]. A 2010 Ipsos-Reid survey showed that 73% of Canadians regularly take natural health products (NHPs) like vitamins and minerals, herbal products, and homeopathic medicines [114]. Health Canada defines natural health products under the Natural Health Products Regulations as:


Natural Health Products must be safe to use as OTC products and not need a prescription to be sold [115]. Natural products, compounds and active ingredients derived from natural sources or totally synthesized and needing a prescription are regulated as drugs under the Food and Drug Regulations [115].

#### *5.2.2. European Union*

Herbal supplements and nutritional supplements are not regulated on a harmonized EU wide basis and remain under the control of the relevant medical institutions of the individual EU member states.

#### **5.3. Cosmeceuticals**

that is the basis on which manufacturers/distributors have concluded that a dietary supplement containing a new dietary ingredient will reasonably be expected to be safe

**•** The U.S. Congress defined the term "dietary supplement" and both of the terms "dietary ingredient" and "new dietary ingredient" as components of dietary supplements in the DSHEA. A dietary supplement is a product taken by mouth that contains a "dietary

**•** In order to be a "dietary ingredient," it must be one or any combination of the following

**•** A "new dietary ingredient" is one that meets the above definition for a "dietary ingredient"

**•** Dietary supplements can also be extracts or concentrates, and may be found in many forms such as tablets, capsules, softgels, gelcaps, liquids, or powders [88]. They can also be in other forms, such as a bar, but if they are, information on their label must not represent the product as a conventional food or a sole item of a meal or diet [88]. Whatever their form may be, the DSHEA places dietary supplements in a special category under the general umbrella of "foods," not drugs, and requires that every supplement be labeled a dietary supplement.

In Canada, the use and sale of natural health products (NHPs) is on the rise [8]. A 2010 Ipsos-Reid survey showed that 73% of Canadians regularly take natural health products (NHPs) like vitamins and minerals, herbal products, and homeopathic medicines [114]. Health Canada

Natural Health Products must be safe to use as OTC products and not need a prescription to be sold [115]. Natural products, compounds and active ingredients derived from natural sources or totally synthesized and needing a prescription are regulated as drugs under the

Herbal supplements and nutritional supplements are not regulated on a harmonized EU wide basis and remain under the control of the relevant medical institutions of the individual EU

defines natural health products under the Natural Health Products Regulations as:

**•** Traditional medicines such as traditional Chinese medicines

**•** Other products like amino acids and essential fatty acids [115].

and was not sold in the U.S. in a dietary supplement before October 15, 1994.

under the conditions of use recommended or suggested in the labeling [87].

ingredient" intended to supplement the diet.

22 Using Old Solutions to New Problems - Natural Drug Discovery in the 21st Century

substances:

*5.2.1.2. Canada*

**•** Vitamins and minerals

**•** Homeopathic medicines

Food and Drug Regulations [115].

*5.2.2. European Union*

member states.

**•** Herbal remedies

**•** Probiotics

Although the term is not recognized by the US Food and Drug Administration (FDA) or by the European Medicines Agency (EMA), it has been widely adopted by the cosmetics industry, which is rapidly expanding in spite of global economic woes in recent years [116]. The global cosmeceuticals market references the seven most developed markets including the U.S. and the top five European countries, namely the UK, France, Germany, Italy and Spain; as well as Japan [116]. In 2011, the global cosmeceuticals market was estimated to be worth \$30.9 billion (with the aforementioned European countries accounting for approximately 65% of overall revenues) and is expected to reach \$42.4 billion by 2018 [116]. Three major categories have been noted in the cosmeceutical industry including skin care, hair care, and others, with the skin care segment accounting for the largest share of the market at 43% [117]. Dominated by antiaging products, the skin-care market is expected to contribute significantly to future growth based on the aging populations in the top seven aforementioned markets [116].

Cosmeceuticals are topically applied and represent a hybrid of cosmetics and pharmaceuticals usually containing vitamins, herbs, various oils, and botanical extracts or a mixture thereof including antioxidants, growth factors, peptides, anti-inflammatories/botanicals, polysacchar‐ ides, and pigment-lightening agents [117, 118]. The combination of cosmetics and foods resulted in products termed nutricosmetics. Nutricosmetics are foods and supplements claiming cosmetic effects with major ingredients like soy isoflavone proteins, lutein, lycopene, vitamins (A, B6, E), omega-3 fatty acids, beta-carotene probiotics, sterol esters, chondrotin and coenzyme Q10 [119, 120]. These compounds act as antioxidants and the respective nutricos‐ metics containing them are being promoted for their skin care properties as for instance in antiaging by fighting free radicals generated as a by-product of biochemical reactions through skin exposure to the sun [119].

#### *5.3.1. North America*

#### *5.3.1.1. United States of America*

In the US, products that can be put in both the cosmetics and drugs category, such as cosmetic products with active ingredients which claim therapeutic use, require New Drug Application (NDA) approval or must comply with the appropriate monograph for an (OTC) drug. Moreover, the FDA also has specific guidelines for Good Manufacturing Practice (GMP) for cosmetics [116].

While the *Federal Food, Drug, and Cosmetic Act (FD&C Act)* does not recognize the term "cosmeceutical", the cosmetic industry uses this word to refer to cosmetic products that have medicinal or drug-like benefits [118]. The FD&C Act defines drugs as those products that cure, treat, mitigate or prevent disease or that affect the structure or function of the human body [121]. Under the FD&C Act, cosmetic products and ingredients, with the exception of color additives, do not require FDA approval before they go on the market [121]. Therefore, while drugs are subject to a review and approval process by the FDA, cosmetics are not approved by the FDA prior to sale. However, when a product makes a therapeutic claim (e.g. to prevent or treat disease), it is classified as a drug and therefore requires evaluation by the FDA's Center for Drug Evaluation and Research (CDER) and a drug identification number (DIN) before it can be sold.

#### *5.3.1.2. Canada*

In Canada, the term "cosmeceutical" (used to describe a cosmetic product with pharmaceuti‐ cal-like benefits) is not employed by Health Canada [122]. Therefore cosmeceuticals fall under either cosmetics or drugs (depending on the claims made and/or the composition of the product) and are subject to the provisions of the Food and Drugs Act and its Cosmetic Regulations regarding composition, safety, labeling and advertising and they are subject to the provisions of the Consumer Packaging and Labeling Act and Regulations [122]. The three most significant features of the Canadian cosmetic regulatory system are mandatory notifica‐ tion of all cosmetic products, safety of ingredients and products, and product labeling [122]. According to Health Canada, a "cosmetic" is defined as *"any substance or mixture of substan‐ ces, manufactured, sold or represented for use in cleansing, improving or altering the complexion, skin, hair or teeth and includes deodorants and perfumes"* [122].

#### *5.3.2. European Union*

In Europe, EMA guidelines place a clear demarcation between drugs and cosmetics, whereby a cosmetic is a product that is to be applied topically with an intended cosmetic function and products cannot fall under both categories, unlike in the US [116]. On November 30th (2009), the new Cosmetic Products Regulation, EU Regulation 1223/2009 was adopted, replacing the Cosmetics Directive [123]. With the new Cosmetics Regulation, Europe claims to have a robust, internationally recognized regime, which reinforces product safety taking into consideration the latest technological developments [123]. Most of the provisions of this new regulation will be applicable as of July 11th, 2013 [123].

## **6. Conclusion**

A natural product or secondary metabolite is a pharmacologically or biologically active chemical compound or substance, which is found in nature and produced by a living organism. The lengthy process of natural products evolution has resulted in optimal interactions with biological macromolecules and targets. Historically, natural substances have been the most productive source of active compounds and chemical lead structures. Natural products have traditionally provided a large fraction of the drugs in use today and millions of terrestrial and marine plants, organisms and microorganisms provide an immense resource to discover unprecedented novel bioactive scaffolds. These have the potential to serve as medical treat‐ ments or templates for new therapeutics and may be suitable for production via a synthetic routes or in a heterologous system like *E. coli.* About half of the agents in today's arsenal of marketed drugs are derived from biological sources with the large majority being based on terrestrial natural product scaffolds. Approximately 50% of the new drugs introduced since 1994 were either natural products or derived from natural products. As of today, only a very small fraction of bioactive structures of potential therapeutic relevance from plants, microbes, and marine organisms have been chemically analyzed or examined in a broad panel of screening models or bioassays. The discovery of valuable therapeutic agents from natural sources continues in the 21th century by reaching into new and untapped terrestrial and marine source organisms as the chemical novelty associated with natural products is higher than that of structures from any other source.

There is growing awareness of the limited structural diversity in existing compound collec‐ tions and the extreme chemical diversity, the high biological potency, and the potential to frequently discover drug-like characteristics in natural products. Therefore, they constitute a valuable platform for the development of new therapeutics for a variety of indications, al‐ though they may still not contain enough versatility to yield suitable treatments for all herit‐ able human diseases.

As some major pharmaceutical companies terminated their natural product programs, the future role to discover and feed candidates into the development pipelines will reside increasingly with research institutes and small biotech companies. Over a hundred new drug candidates from natural sources like plants, bacteria, fungi and animals or obtained semisynthetically are in clinical development with a similar number in preclinical development. They target a variety of indications, mainly cancer and infectious diseases (bacterial, viral, fungal, and parasitic) but also other therapeutic areas such as cardiovascular diseases, neurological illnesses and depression, metabolic diorders and inflammatory diseases.

Natural products, although a valuable and precious resource, also come with their fair share of challenges concerning the provision of sufficient amounts of pure enough material for discovery and development activities. As mentioned earlier, such apprehensions are based on the threat of losing potentially valuable natural sources through extinction resulting from deforestation of large landmasses, environmental pollution in remote areas as well as global warming. Countries are also increasingly protective of their natural assets in flora and fauna and may not authorize the collection of sample species without significant demands and very difficult negotiations. The regulatory requirements for different product categories containing natural substances like pharmaceuticals, nutraceuticals, and cosmeceuticals vary from rather stringent over generous to non-existent at an international level. Even if natural health products or dietary supplements are considered as or expected to be safe, they may still carry potential risks in themselves or through interactions with prescription or OTC drugs. There‐ fore, the discovery and development of natural products require cientific validation and sufficient pharmacoepidemiological evidence to support their safety and efficacy.
