ISURA, in collaboration with the Technical University of Braunschweig, recently published an article in the journal – Plants, on herbal authentication using a combination of chemical and biological test methods. The article showcases ISURA’s capabilities in the areas of morphological identification, HPTLC fingerprinting, advanced mass spectrometry, and DNA sequencing.

The published test methods will help find adulterants undetectable by traditional means such as HPTLC and morphological identification. Furthermore, the data has been submitted to the National Center for Biotechnology Information (NCBI) to prevent future misidentification of horsetail plants through DNA sequencing.

A Multi-Pronged Technique for Identifying Equisetum palustre and Equisetum arvense—Combining HPTLC, HPLC-ESI-MS/MS and Optimized DNA Barcoding Techniques

Plants 2022, 11(19), 2562; https://doi.org/10.3390/plants11192562

Abstract

The most prominent horsetail species, Equisetum arvense, has an array of different medicinal properties, thus the proper authentication and differentiation of the plant from the more toxic Equisetum palustre is important. This study sought to identify different samples of E. arvense and E. palustre using three analytical methods. The first method involved the use of HPTLC analysis, as proposed by the European Pharmacopoeia. The second, HPLC-ESI-MS/MS, is capable of both identification and quantification and was used to determine the Equisetum alkaloid content in each sample. A third method was DNA barcoding, which identifies the samples based on their genetic make-up. Both HPTLC and HPLC-ESI-MS/MS proved to be suitable methods of identification, with HPLC-ESI-MS/MS proving the more sophisticated method for the quantification of alkaloids in the Equisetum samples and for determining the adulteration of E. arvense. For DNA barcoding, optimal primer pairs were elucidated to allow for the combined use of the rbcL and ITS markers to accurately identify each species. As new DNA marker sequences were added to GenBank, the reference library has been enriched for future work with these horsetail species.

Direct Link to Abstract in Plants: https://www.mdpi.com/2223-7747/11/19/2562

As with other health products, the manufacture, sale, and distribution of natural health products (NHP) is now truly international. Though the market may be global, the regulation of NHPs is not, with most countries having different regulatory frameworks for these types of products. Given the complexity of the sector and differences between the various regulatory approaches, comparing national approaches does not make for easy reading. As with a previous article comparing the approaches taken between Canada and the United States [https://isura.ca/2022/04/12/comparing-nhp-regulations-from-canada-and-the-usa/] this article will provide a high-level comparison of the regulatory approaches for Canada and Australia. It will explore some common features:

• Terminology and classification
• Who manages the regulations?
• How are the regulations applied?
• What claims/use can products make?
• How they must be made and inspected?
• What must be on the product labels?

Links to resources that provide more details about each regulatory approach can be found at the end of the article.

Terminology and Classification

Both Canada and Australia take a similar approach in grouping different types of products under an umbrella term – Natural Health Products in Canada and Complementary Medicines in Australia. These terms essentially capture the same types of products in each country notably vitamins, minerals, nutritional substances, probiotics, traditional medicines, and herbal medicines. Though the regulations are not the same, internationally both countries are considered leaders in the field and in many ways take similar approaches.

In Canada, a specific set of regulations – the Natural Health Products Regulations (NHPR) implement the law called the Food and Drugs Act. Under the law, NHPs are considered to be a subset of drugs. In Australia, complementary medicines are captured by a specific set of regulations and guidelines under the auspices of the Australian Therapeutic Goods Act (ATGA). Unlike the USA which considers most of these products as a type of food, both Australia and Canada regulate the NHP/Complementary Medicines category as a type of drug or therapeutic good.

Who manages the regulations?

In Canada, as with most other types of health products, NHPs are primarily regulated by the federal government. The responsible department is Health Canada (HC), and its primary centre of excellence, the Natural and Non-Prescription Health Products Directorate (NNHPD). The NNHPD is responsible for issuing product licenses, site licenses, as well as conducting post-market health hazard evaluations and providing policy support to post-market operations. The organizations responsible for post-market operations are the Marketed Health Products Directorate (MHPD), which is responsible for adverse drug reaction monitoring, and the Regulatory Operations and Enforcement Branch, which is responsible for compliance and enforcement actions (a role it also plays for the majority of other therapeutic products).

As with Canada, in Australia the regulation of complementary medicines is primarily the responsibility of the national government through the Therapeutic Goods Administration (TGA). Many different parts of the TGA as well as other agencies and departments of the commonwealth government have responsibilities for the regulation of complementary. The primary responsibility lays with the Complementary Medicines and Over the Counter Medicines Branch Office, with the Manufacturing and Quality Branch overseeing certification of manufacturing sites and processes.

How are the regulations applied?

In both Canada and Australia, criteria are used to determine whether a product is, or is not, in compliance with the law. Though different approaches are taken, in each country, a pre-market application and licensing process is used to determine if a product meets standards prior to it being sold in the market.

In Canada, all product applications need to be evaluated by Health Canada before being approved with the process dependent on the type of application e.g., attestation to a monograph, requiring full review, etc. In Australia, there is no single regulatory “class” of product, with complementary medicines either being categorised as a listed medicine, an assessed listed medicine or a registered medicine – the categories are determined largely by the product claim that can be made and its safety profile. The review process reflects this with:

• listed medicine approved online through a system called the electronic listing facility (ELF),
• assessed listed medicines approved online but with assessment of evidence for efficacy made by the TGA premarket, and
• registered medicines undergoing a full evaluation of all aspects by the TGA premarket.

The vast majority of approved complementary medicines (approximately 11,000) are categorised as listed medicine with registered medicines numbering under 100 with many of those grandfathered before the ATGA came into force. The category of assessed listed is still new with very few being approved and, on the market,

In both countries, a risk-based approach is taken with required monitoring for products on the market. Each country has specific requirements for reporting adverse events and side effects. Again, this is a very high-level overview, and both sets of regulations are far more detailed.

A major operational difference between Canada and Australia is that the Australian regulations are completely cost recovered with sponsors required to pay a fee for implementation of the regulatory framework. This includes product listing, assessed listed, registration and site audits discussed in the next section. Though cost recovery was identified as an important step when the Canadian NHPR were being developed, this currently does not occur in Canada for NHPs with funding coming from government budget. Health Canada has identified developing and implementing a cost recovery regime in the coming years as a priority.

What claims can products make?

In Canada, NHPs are the same as any other non-prescription health product in terms of the claims they may make. They must make a claim, that is, an NHP cannot be sold as a medicine without any supporting proof of what it does or investigation into its safety. The use may come from the full gamut of treatment, altering function, risk reduction and health promotion. NHPs can also make claims based on traditional forms of health and healing such as western herbalism or traditional Chinese medicines. The type of claims must be reflected in the type, quantity, and quality of supporting evidence submitted for review by Health Canada. For example, the traditional evidence that is accepted by Health Canada is that which reflects scientific principles of reproduceable results, integrity in the dosage form and consistency in the patient population over decades of recorded study. For any use, additional data must be produced and considered to support more specific clinical claims. Health Canada has developed specific review pathways including the use of monographs to facilitate this process.

Australia takes a similar approach to Canada for complementary medicines with products able to make the full gamut of self-care claims based on the quantity and quality of evidence provided by the sponsor. Again, like Canada, traditional as well as modern clinical evidence are accepted with details outlined in the Australian Regulatory Guidelines for Complementary Medicines (ARGCM). The “claim permitted” reflects the extent of review with

• listed medicines limited to lower-level indications such as traditional use and health promotion,
• assessed listed medicines include more treatment related indications, and
• registered complementary medicines allowed to have full treatment indications.

Both of these approaches to “evidence required to support claims” means that there are no disclaimers on the labels of either Canadian or Australian products related to the product’s safety, efficacy, or quality.

How must these products be made and inspected?

Both countries have specific requirements for Good Manufacturing Practices (GMPs) which manufacturers, importers and distributors must ensure are being followed in order to maintain required site licences in Canada or site audit in Australia. However, each country takes a very different approach to how the regulations are applied.

In Canada, with its pre-market approach, a site licence must be issued for the manufacturing facility before a NHP is allowed to come to market. This is typically an unvalidated review approach as there is no requirement for a systematic on-site inspection required. In Australia, as with all other therapeutic goods, all manufacturing sites must have passed an onsite audit by the TGA or other recognised regulatory agency. These inspections are based on the principles of the Pharmaceutical Inspection Cooperation Scheme (PICs). Irrespective of whether the product is considered listed, assessed listed or registered, a successful site audit is required before any product approval process can even begin. This Australian approach is widely considered to be the international gold standard.

What must be on the product labels?

Given that both Australia and Canada have established, drug/therapeutic good-based regulations, it is not surprising that they have very well-defined requirements for product labeling.

These comprehensive labeling requirements for labels include information such as:

• all ingredients (medicinal and non-medicinal),
• quantities,
• dosage form,
• recommended dose and duration of use,
• indications/purpose of use, and
• risk information such as potential drug interactions, side effects contraindications, allergens

In addition, the regulations in both countries require that a label contains a number identifying that they have been approved by the regulator. In Canada, this is an 8-digit Natural Products Number (NPN) or DIN-HM for homeopathic medicines. For Australia, this is shown by an Aust L or Aust R number. Both countries require details of the manufacturer, supplier, and distributor to be on the label.

Guidelines also deal with how information must be presented on the label. As you can imagine, there are a great deal of similarities between each country’s approach. While Canada currently does not require a product fact table, this will become mandatory under the new regulations coming into force in the coming years[1].

As with all products sold in Canada, this information must be presented in both official languages, English and French. Health Canada is currently exploring how labeling for NHPs can be improved – learn more in this ISURA article: Improved Labelling for Natural Health Products – Health Canada Initiative in the Articles & Info section of the ISURA website: isura.org.

Australia takes a different approach by only recommending the use of tabulated Critical Health Information for listed medicines rather than making such information mandatory on product labels.[2] Since listed medicines make up the vast majority of approved complementary medicines in Australia, this means that the majority of products in this category currently do not require the equivalent of a product facts table.

Final thoughts

Australia and Canada have long been considered global leaders in the regulation of complementary medicines/natural health products. Both countries consider them as a specific category of medicines rather than foods. Many other regulators look to these countries’ successes and failures in developing national regulatory frameworks. Though similar in many ways the two countries do differ in some aspects of their approach to regulating these types of products. Australia has focused on quality and manufacturing establishing the gold standard in Good Manufacturing Practices and utilizing required site audits as an essential part of the regulations. Canada has focussed on product evaluation and the evaluation of evidence supporting claims made for a product including establishing an extensive set of NHP monographs exclusively developed as regulatory tools. The question now is what next?

Though both countries’ regulations are still considered at the vanguard of the regulations for this category, it has been more than 20 years since both approaches were established. In the past couple of decades much has changed with the emergence of a truly international market; the increase in global manufacturing; online sales; changes in how these products are used; advances in research and innovation; and the role that natural health products/complementary medicines now have in the larger health care system. In response, the regulations in both countries have evolved to better reflect the current reality and specific domestic priorities. It will be interesting see how things develop over the coming years.

The information in this article provides a general comparison between the regulatory approaches of Canada and Australia. If you would like more information about specific areas mentioned above or specific topics such as advertising/marketing regulations, you can find more details about the Canadian approach at https://www.canada.ca/en/health-canada/services/drugs-health-products/natural-non-prescription/regulation.html and the Australian approach at How we regulate | Therapeutic Goods Administration (TGA).

Download a PDF version of this article Here.

About the author:

Michael Smith trained as a pharmacist and as a naturopathic doctor. He is recognized internationally as an expert in natural health products and complementary & alternative medicine. For more than 10 years, he worked in senior regulatory positions at the then Natural Health Products Directorate, Health Canada, and the Therapeutic Goods Administration in Australia. In addition to his international work as a consultant, he is an Adjunct Professor at the National Center for Natural Products Research at the University of Mississippi, USA and an Adjunct Associate Professor at the National Centre for Naturopathic Medicine at Southern Cross University, Australia. Michael is a member of ISURA’s Scientific Advisory Committee.

[1] https://canadagazette.gc.ca/rp-pr/p2/2022/2022-07-06/html/sor-dors146-eng.html

[2] https://www.legislation.gov.au/Details/F2017C00744

ISURA is pleased to be a Diamond Sponsor for the upcoming NHPRS of Canada virtual Annual Conference in partnership with the Institute of Nutrition and Functional Foods. The virtual conference takes place Monday to Tuesday over two weeks. This year’s theme is Food-Derived NHPs in Health & Disease. Registration is online. Reserve your place now.

What is this new initiative?

On June 25, 2021, the Government of Canada posted, in Canada Gazette 1 (CG1), a number of proposed changes to the Natural Health Products Regulation mainly focused on labelling requirements for this category of products. As is routine with proposed changes, Health Canada also launched a consultation process called Proposed Regulations Amending the Natural Health Products Regulations – Improving Labelling for Natural Health Products. The aim of this consultation is to “address poor communication of key information on health products labels that can lead to incorrect purchases and preventable harms”. More information about the proposed changes and the consultation can be found at https://gazette.gc.ca/rp-pr/p1/2021/2021-06-26/html/reg4-eng.html

Is this related to the Plain Language Labelling initiative for non-prescription medicines?

Plain language labelling (PLL) is a Health Canada initiative that aims to support consumers in making informed choices about health products through clearer and more concise labels. When the PLL initiative was launched for self-care products it was limited to non-prescription medicines with Natural Health Products (NHP) specifically not included. The new initiative launched on June 25, 2021, is the evolution of the original PLL initiative with proposals being made specific to NHPs so that they are “in alignment with the rules already established for comparable non-prescription drugs (NPDs)”.

These label changes are the first major part of the creating a cohesive self-care framework for health products. More information about the self-care framework can be found at selfcareproducts-produitsautisoins@hc-sc.gc.ca

How does Health Canada define a “label”?

In the Regulatory Impact Analysis Statement (RIAS) included in the consultation, Health Canada describes a label as:

“an all-encompassing term that covers the affixed information on the actual health product package and other information that is made available to consumers and health professionals, including the product box and any inserts, tags, or leaflets. Important information should be clearly and consistently displayed so consumers can make comparisons between products, properly selected and use of NHPs, be fully informed of their benefits and harms, and be able to avoid preventable harms”

What changes are being proposed by Health Canada?

The proposed labelling changes fall into four basic areas:

• Inclusion of a Products Facts Table: a requirement that important product information such as ingredients, indication, risk information be presented in a table on the label with certain exemptions for very small packages, relatively low risk products and products with a short duration of use.
• Labelling of Food Allergens, Gluten and Aspartame: aligning with the existing food definitions, require products that contain a “priority food allergen”, gluten or aspartame to state the source of the substance on the product’s label.
• Clearly and Prominently Displayed Label Text: improved legibility requirements for label text by requiring such things as minimum type size, font types and contrast. Similar exemptions will exist as those identified for the Products Facts Table above.
• Modernized Contact information: removing the requirement for a postal address of the manufacturer or importer and instead the label must display an email address, telephone number or website address which must be within the Products Facts Table unless exempted for one of the reasons mentioned above.

 The above information only provides a high-level overview of what is being proposed. More details can be found in the RIAS or the proposed regulatory changes both of which can be found at the website noted above.

Is this a one size fits all initiative or will it depend on the type of Natural Health Product?

Health Canada recognises that in some cases there could be practical challenges in complying with these regulations and consequently have included a number of “exemptions from use” of a Products Facts Table. These include:

• If there is no outer label and has a small inner label (77.5cm2 or less);
• Recommended duration of use is one day or less;
• Contains three or fewer dosage units; and
• The NHP has a localized rather than systemic effect and is for administration in the oral cavity, on the skin or as a throat lozenge or for topical aromatherapy.

In addition, during a technical briefing informing stakeholders of the posting of these proposed changes in CG1, Health Canada indicated that they were considering additional flexibility regarding the Products Facts Table for products with 4 or more ingredients.

What evidence is proposed to support these improvements?

 Health Canada identifies several sources of evidence in the RIAS in support of this initiative. These include:

• observations from changes to non-prescription drug labelling seen in Canada and internationally;
• identification of risk associated with this category of health products such as potential drug interactions and adverse events;
• preferences identified by consumers during the consultation process;
• research published in peer review journals identifying the role labels play in consumer decision making around Natural Health Products;
• information from reported adverse events where NHPs potentially have caused harm including cases where labelling errors or confusion were suspected of being the issue; and
• findings from the report from Commissioner of the Environment and Sustainable Development within the Office of the Auditor General on the management of the NHP regulations published in April 2021. See our post on this report – Read More.

Although this evidence does not necessarily show a link between improved labelling and a decrease in incidence of harm, the argument put forward by Health Canada is that since NHPs play an increasing role in the health of Canadians, this new labelling initiative has the potential for reducing risks from NHPs.

How will this new approach to improved labelling for Natural Health Products be rolled out?

 Recognising that these changes may require extensive changes to NHP labels, Health Canada is proposing a relatively long implementation period of three years after the date of implementation of the new requirements. In addition, all NHPs on the market at the time of these changes coming into force will have an additional three-year period before compliance is required with these new amendments.

What kind of consultations has Health Canada conducted with stakeholders?

The RIAS outlines the consultation process which took place over the past 4 years including:

• feedback from the proposed self- care framework which began in April 2016;
• results of an online consultation between September and October 2016;
• comments made from cross country in-person consultations in 2017; and
• technical briefings with key stakeholder groups throughout the process.

What will be the financial costs and environmental impact of implementing these improvements?

In the RIAS, Health Canada states that additional impact on the environment would be minimal. In making this statement, several assumptions are made such as manufacturers adopting peel back labels, inserts or leaflets instead of increasing package size. It also concludes that these new changes will result in little or no additional costs over and above what companies would normally invest in keeping labels current.

While many industry stakeholders were concerned that these proposed labelling changes would be a repeat of the negative impact they say occurred for non-prescription medicines, this was before the full proposal was published in Canada Gazette 1. We will see if their concerns are addressed now that the full proposal has been published.

Final Thoughts

Any initiative that improves Canadians’ ability to make informed decisions about whether to include or not include NHPs in their health care options should be supported and championed. What the evidence also shows is that that accurate product labels presented in a standard format are important tools for consumers to use when making health care decisions including those about NHPs.

As with any new regulations. there will be issues that arise during their development and upon initial implementation. These issues will need to be resolved. Two immediate questions come to mind:

First –Is this the best time for Health Canada to be prioritizing improvement to the labelling of NHPs? Though intuitively, and as identified in the RIAS, these changes may help consumers make health care decisions related to NHPS, there is limited information about whether improved labelling for NHPs will help decrease harm to Canadians taking NHPs. There is far more robust evidence identifying the risk posed to consumers through inadequate compliance and enforcement, and by not ensuring high quality products through good manufacturing practices. Both of these issues were identified as being more impactful than improvements to labelling in a recent report from the Commissioner for Sustainability and the Environment. Given this, any proposal aimed at improving product labels must be made in tandem to improvements in these other more pressing areas.

The second question relates to the practicalities of implementing these changes for a sector as complex as the NHP market notably around the requirements for the Products Facts Table. While having the Table will likely prove helpful for products with a single or limited number of ingredients, it could be physically impossible to include, in a useful way, all the information required for multi-ingredient products such as multi-vitamins or those used in many traditional medicines. Internationally, rather than require a Products Facts Table, Australia only encourages the majority of complementary medicines to include a Products Facts Table.[1] In the European Union, food supplements, such as NHPs, are exempted from the requirements for the food regulations.[2] While the United States does require that the label of a dietary supplement includes a Supplements Facts Table, the required information that it must contain is quite limited. It is important to note, and encouraging to see, that the issue of multi-ingredient products has already identified by Health Canada and additional flexibilities, including the impact on products with more than four ingredients, are already being explored.

Download a PDF of this post here.

About the author:

Michael Smith trained as a pharmacist and as a naturopathic doctor. He is recognized internationally as an expert in natural health products and complementary & alternative medicine. For more than 10 years, he worked in senior regulatory positions at the then Natural Health Products Directorate, Health Canada and the Therapeutic Goods Administration in Australia. In addition to his international work as a consultant, he is an Adjunct Professor at the National Center for Natural Products Research at the University of Mississippi, USA and an Adjunct Fellow at the National Institute of Complementary Medicine at Western Sydney University, Australia. Michael is a member of ISURA’s Scientific Advisory Committee.

[1] https://www.tga.gov.au/medicine-labels-guidance-tgo-91-and-tgo-92

[2] https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32002L0046&from=DA