Melody Harwood, B.Sc.03.01.04
Dietary supplements are regulated and defined differently across the globe. With the promulgation of new regulations on January 1st this year, Health Canada officially added a new term to the global list of synonyms for such commodities: Natural Health Products (NHPs). Developed with the intent of providing Canadian consumers with ready access to NHPs that are safe, effective and of high quality, the new Natural Health Products Regulations (the Regulations) are applicable to the sale, manufacture, packaging, labeling, importation, distribution and storage of NHPs, and will be administered by the newly formed Natural Health Products Directorate (NHPD) within Health Canada.
Recognizing the importance of nutrition and the increasing documentation of benefits of dietary supplements to health promotion and disease prevention, the Dietary Supplement Health and Education Act of 1994 (DSHEA) was enacted by the U.S. Congress to amend the Federal Food, Drug, and Cosmetic Act (FFDCA) to create standards with respect to dietary supplements. DSHEA amended the FFDCA with provisions delineating the distinct regulation of dietary supplements as products other than conventional foods or drugs.
In Canada, such products previously were regulated either as foods or as drugs under the Food and Drugs Act and Regulations, with drugs requiring pre-market approval and the issuance of a Drug Identification Number (DIN). Although encompassed under the Food and Drugs Act (the Act), the NHP Regulations are essentially independent of the Food and Drug Regulations and provide for a unique regulatory regime for these products as sold in Canada. As NHPs are not defined in the Food and Drugs Act, in order to be incorporated under the Act, NHPs are regulated as a subset of drugs, and several provisions from the Food and Drug Regulations were integrated to allow for proper administration of the NHP Regulations.
Under the Regulations, the definition for a NHP comprises two components: a substance component and a function component. The substance component incorporates various substances permitted for sale as a NHP, either singly or in combination, and includes herbal remedies, traditional and homeopathic medicines (HM) and a schedule of express inclusions comprising materials derived from plants, algae, bacteria, fungi or non-human animal material; amino acids; essential fatty acids; probiotics; minerals; several vitamins; and duplicates of the natural ingredients, where applicable. Excluded from the definition are antibiotics, substances administered by puncturing the dermis, substances regulated under the Tobacco Act, and several substances regulated under the Food and Drug Regulations, such as radiopharmaceuticals, biologics and drugs.
The function component of the NHP definition includes those permitted substances sold or represented for use in humans: (1) for the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state or its symptoms; (2) for restoring or correcting organic functions; or (3) for otherwise modifying organic functions in a manner that maintains or promotes health.
In the U.S., DSHEA defines acceptable dosage forms of dietary supplement products as tablets, capsules, soft gels, gelcaps, liquids, powders, or other forms such as bars, provided they are not represented as a conventional food item or as a sole item of a meal or of the diet. In Canada, permitted forms of NHPs are not expressly defined in the Regulations; however, the NHPD recognizes the commonly sold forms of these products, such as capsules, pills, tablets, powders, or liquids, and also considers certain other forms, including bars and gums, as acceptable forms, without excluding other food items, such as wafers or beverages, provided that such product forms are not intended to be "primarily consumed to provide nourishment, nutrition or hydration."
One of the main components of the Regulations is product licensing. Under the new Regulations, all NHPs will be required to undergo pre-market review to obtain a product license and a corresponding Natural Product Number (NPN) or, in the case of homeopathic medicines, a DIN-HM. This varies from the situation in the U.S. in that, under the DSHEA, unless a dietary supplement contains a new dietary ingredient (NDI), a manufacturer is not required to obtain approval from the U.S. Food and Drug Administration (FDA) prior to marketing its product, although other provisions must still be satisfied to ensure a reasonable expectation of safety. Rather, the burden of proof is on the FDA to determine that a marketed dietary supplement product is unsafe or adulterated prior to initiating action to restrict product use or to remove the product from sale.
Generally, the Product License Application (PLA) must contain information to allow the NHPD to evaluate the safety, efficacy and quality of the NHP, as well as the proposed label text(s); however the extent of the required information depends on the submission type. The NHPD has developed a Compendium of Monographs for use in the evaluation of the safety and efficacy of medicinal NHP ingredients. Compendial product applications include ingredients for which a monograph has been included in the NHPD Compendium, and hence do not require additional data supporting safety or efficacy, and beginning July 1, 2004, are subject to a 60-day disposition period. Non-compendial products require a full review and may incorporate traditional or non-traditional claims. Other types of applications include those for transitional products [NHPs already holding a (DIN)] and for HMs. Should a foreign applicant submit a PLA, a representative in Canada must be listed to whom notices may be sent.
Once a product is issued a NPN, the licensee is required to keep records containing a list of all ingredients and enough information to issue a lot or batch recall, if required, for at least one year after the expiry date of the NHP. Additionally, each licensee is required to implement and maintain a system for adverse reaction (AR) reporting for each NHP on the market.
In addition to providing data on the safety, efficacy and quality of NHP ingredients, each applicant must provide information regarding the site of manufacture, packaging, labeling, distribution or importation, with corresponding Site License (SL) numbers, acquired through the submission of a SL Application (SLA).
Similar to the FDA's proposed rule, "Current Good Manufacturing Practice in Manufacturing, Packing, or Holding Dietary Ingredients and Dietary Supplements for Dietary Supplements," which applies to all entities that manufacture, package or hold dietary ingredients and dietary supplements for distribution in the U.S., included in the NHP Regulations are measures for good manufacturing practices (GMPs) designed to help ensure product quality control by setting standards and practices for product manufacturing, specifications, storage, handling and distribution, and by requiring adherence to set standards and procedures. Applicants must demonstrate compliance with NHP GMP requirements before being issued a SL.
The Regulations also lay out provisions for clinical trials conducted with NHPs, including principles of good clinical practice (GCP), roles and responsibilities of sponsors and requirements for protocols, product labeling, record keeping, adverse event reporting, site information and trial application packages, including research ethics approval.
As mentioned, NHPs were previously regulated in Canada under the Food and Drug Regulations as food products, which could not bear health claims, or as drugs with authorized claims and directions for use. The situation for products regulated in the U.S. under DSHEA is similar, such that a product represented for sale as a dietary supplement may not claim to diagnose, mitigate, treat, cure or prevent a specific disease or class of diseases, although various authorized or qualified health claims may be permitted pending approval from the FDA. Under the NHP Regulations, the opportunity for health claims is better accommodated.
A regulatory approach of requiring any dietary supplement or NHP claiming potential health benefits to meet existing drug legislation could be considered somewhat restrictive, onerous and irrelevant. Realizing the importance for conveying sound, scientific evidence of the benefits of NHPs to consumers, the NHP Regulations provide for various types and categories of product claims based on the credibility, strength and quality of the evidence used to support the claim.
The NHPD defines a claim as "a statement that indicates the intended beneficial effect of a NHP when used in accordance with the labeled dose (i.e., recommended dose), duration of use and route of administration." The permitted types of claims include treatment claims, which relate to the diagnosis, treatment and mitigation or prevention of a disease, disorder, or abnormal physical state or its symptoms in humans. These claims must be supported by the totality of scientific evidence. Risk reduction claims are the second type of permitted claims. Best supported by well-designed observational studies, such as prospective cohort studies, risk reduction claims are based on the relationship between a medicinal ingredient and the reduction in the risk of developing a certain disease; for example, by the alteration of a major risk factor or other contributing factor involved in the development of disease. Another type of permitted claim-structure/function-relates to the effect or support of a NHP ingredient on the structure or anatomical, physiological or mental function in the human body. Examples of structure/function claims include "Maintains healthy gums" or "Reduces blood cholesterol," and where adequately supported by evidence, may include broad statements related to the promotion of overall health.
There are two categories for claims: traditional use claims and non-traditional use claims, each with different requirements for efficacy. Traditional use claims refer to the practices based on the theories or beliefs of indigenous or different cultures used in the maintenance of health or the prevention, diagnosis or treatment of physical and/or mental illness for at least 50 consecutive years. Traditional use claims must be supported by at least two independent references. Non-traditional use claims must be supported by scientific evidence, meaning the requirements are more stringent than for traditional use claims. However, the evidence for non-traditional use claims may be acquired from a wide range of sources, including clinical studies, pharmacopoeias and textbooks, peer-reviewed published articles, pre-clinical studies, reputable regulatory authority reports and expert opinion reports. The strength of evidence for non-traditional claims is graded by level of evidence from human studies, with well-designed randomized, controlled trials bearing the greatest amount of strength, and claims to treat more serious health conditions requiring support by the strongest level of evidence. This system could be compared to the recently published evidence-based ranking system for scientific data for qualified health claims in the U.S. (Guidance: Interim Evidence-Based Ranking System for Scientific Data), which would rank or grade the scientific evidence supporting a claim [i.e., A (High), B (Moderate), C (Low) or D (Extremely Low)] and provide statements to qualify the claim depending on its grade. The level of scientific evidence for a claim for a NHP is similarly graded, although in pre-issuance of a claim. Claims will not be issued for NHPs without sufficient supporting evidence.
Several transitional provisions are outlined in the Regulations that provide for the sale of products that
are already on the market in Canada, either as a food or a drug. The transition period for site licensing and GMPs is two years (January 1, 2006). Products that have already been issued a DIN, but to which the Regulations could be applied have up to six years to register for a NPN (January 1, 2010). Compliance and enforcement for products without DINs will be prioritized according to a risk-based product category priority approach.
Quintessentially, consumers seek out dietary supplement or natural health products for the purpose of improving their health and overall state of being, and the use of these products is increasing each year. In Canada alone, the market for NHP rose from an estimated (CAD) $1.1-1.8 billion in 2000, to sales of (CAD) $4.3 billion in 2001.
Just as there is no globally accepted term for dietary supplements, neither is there a harmonized set of global regulatory requirements for these products. On an international basis, without a universally accepted regulatory regime, manufacturers of natural therapies have had to comply with varying standards related to safety, efficacy and quality. Regulatory authorities worldwide are realizing the potential positive impact that such products could have on the health of a nation and the frameworks for regulating natural products are shifting to accommodate this change of view. For example, as the U.S. braces for impending changes to its regulations governing dietary supplements, various other jurisdictions are proactively working toward developing comprehensive legislative frameworks for supplement products. Communities such as the EU and Latin America are working toward harmonizing their legislation for dietary supplements and natural health products, although accepted global standards might still be far from realization.
Designed with the goal of providing consumers with products that are safe and efficacious, the NHP Regulations were built on a foundation of sound scientific practice and observation of other regulatory frameworks for such products. Contrary to the previous situation in Canada, the new Regulations provide an even playing field for manufacturers and distributors of NHPs by implementing a unique regulatory category for natural products and developing consistent requirements for the positioning of NHPs for sale in Canada. It has been estimated that the NHP Regulations will affect between 25,000 and 50,000 products on the Canadian market. Although the impact and effectiveness of the Regulations on the state of the industry might not be evidenced for years to come, there is assurance that a framework is now in place in Canada to encourage product safety and quality, while ensuring that consumers have access to efficacious natural health products.NW
About the author: Melody Harwood, B.Sc. (Honors) Toxicology, is a scientific and regulatory consultant with the Food and Nutrition Business Group of Cantox Health Sciences International, Mississauga, Ontario, Canada. She can be reached at 2233 Argentia Road, Suite 308, Mississauga, ON, Canada, L5N 2X7; 905-542-2900; Fax: 905-542-1011; E-mail: mharwood@cantox.com.
Natural Health Products Regulations
Recognizing the importance of nutrition and the increasing documentation of benefits of dietary supplements to health promotion and disease prevention, the Dietary Supplement Health and Education Act of 1994 (DSHEA) was enacted by the U.S. Congress to amend the Federal Food, Drug, and Cosmetic Act (FFDCA) to create standards with respect to dietary supplements. DSHEA amended the FFDCA with provisions delineating the distinct regulation of dietary supplements as products other than conventional foods or drugs.
In Canada, such products previously were regulated either as foods or as drugs under the Food and Drugs Act and Regulations, with drugs requiring pre-market approval and the issuance of a Drug Identification Number (DIN). Although encompassed under the Food and Drugs Act (the Act), the NHP Regulations are essentially independent of the Food and Drug Regulations and provide for a unique regulatory regime for these products as sold in Canada. As NHPs are not defined in the Food and Drugs Act, in order to be incorporated under the Act, NHPs are regulated as a subset of drugs, and several provisions from the Food and Drug Regulations were integrated to allow for proper administration of the NHP Regulations.
Definition of NHP
Under the Regulations, the definition for a NHP comprises two components: a substance component and a function component. The substance component incorporates various substances permitted for sale as a NHP, either singly or in combination, and includes herbal remedies, traditional and homeopathic medicines (HM) and a schedule of express inclusions comprising materials derived from plants, algae, bacteria, fungi or non-human animal material; amino acids; essential fatty acids; probiotics; minerals; several vitamins; and duplicates of the natural ingredients, where applicable. Excluded from the definition are antibiotics, substances administered by puncturing the dermis, substances regulated under the Tobacco Act, and several substances regulated under the Food and Drug Regulations, such as radiopharmaceuticals, biologics and drugs.
The function component of the NHP definition includes those permitted substances sold or represented for use in humans: (1) for the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state or its symptoms; (2) for restoring or correcting organic functions; or (3) for otherwise modifying organic functions in a manner that maintains or promotes health.
In the U.S., DSHEA defines acceptable dosage forms of dietary supplement products as tablets, capsules, soft gels, gelcaps, liquids, powders, or other forms such as bars, provided they are not represented as a conventional food item or as a sole item of a meal or of the diet. In Canada, permitted forms of NHPs are not expressly defined in the Regulations; however, the NHPD recognizes the commonly sold forms of these products, such as capsules, pills, tablets, powders, or liquids, and also considers certain other forms, including bars and gums, as acceptable forms, without excluding other food items, such as wafers or beverages, provided that such product forms are not intended to be "primarily consumed to provide nourishment, nutrition or hydration."
Product Licensing
One of the main components of the Regulations is product licensing. Under the new Regulations, all NHPs will be required to undergo pre-market review to obtain a product license and a corresponding Natural Product Number (NPN) or, in the case of homeopathic medicines, a DIN-HM. This varies from the situation in the U.S. in that, under the DSHEA, unless a dietary supplement contains a new dietary ingredient (NDI), a manufacturer is not required to obtain approval from the U.S. Food and Drug Administration (FDA) prior to marketing its product, although other provisions must still be satisfied to ensure a reasonable expectation of safety. Rather, the burden of proof is on the FDA to determine that a marketed dietary supplement product is unsafe or adulterated prior to initiating action to restrict product use or to remove the product from sale.
Generally, the Product License Application (PLA) must contain information to allow the NHPD to evaluate the safety, efficacy and quality of the NHP, as well as the proposed label text(s); however the extent of the required information depends on the submission type. The NHPD has developed a Compendium of Monographs for use in the evaluation of the safety and efficacy of medicinal NHP ingredients. Compendial product applications include ingredients for which a monograph has been included in the NHPD Compendium, and hence do not require additional data supporting safety or efficacy, and beginning July 1, 2004, are subject to a 60-day disposition period. Non-compendial products require a full review and may incorporate traditional or non-traditional claims. Other types of applications include those for transitional products [NHPs already holding a (DIN)] and for HMs. Should a foreign applicant submit a PLA, a representative in Canada must be listed to whom notices may be sent.
Once a product is issued a NPN, the licensee is required to keep records containing a list of all ingredients and enough information to issue a lot or batch recall, if required, for at least one year after the expiry date of the NHP. Additionally, each licensee is required to implement and maintain a system for adverse reaction (AR) reporting for each NHP on the market.
Other Components of the Regulations
In addition to providing data on the safety, efficacy and quality of NHP ingredients, each applicant must provide information regarding the site of manufacture, packaging, labeling, distribution or importation, with corresponding Site License (SL) numbers, acquired through the submission of a SL Application (SLA).
Similar to the FDA's proposed rule, "Current Good Manufacturing Practice in Manufacturing, Packing, or Holding Dietary Ingredients and Dietary Supplements for Dietary Supplements," which applies to all entities that manufacture, package or hold dietary ingredients and dietary supplements for distribution in the U.S., included in the NHP Regulations are measures for good manufacturing practices (GMPs) designed to help ensure product quality control by setting standards and practices for product manufacturing, specifications, storage, handling and distribution, and by requiring adherence to set standards and procedures. Applicants must demonstrate compliance with NHP GMP requirements before being issued a SL.
The Regulations also lay out provisions for clinical trials conducted with NHPs, including principles of good clinical practice (GCP), roles and responsibilities of sponsors and requirements for protocols, product labeling, record keeping, adverse event reporting, site information and trial application packages, including research ethics approval.
Claims
As mentioned, NHPs were previously regulated in Canada under the Food and Drug Regulations as food products, which could not bear health claims, or as drugs with authorized claims and directions for use. The situation for products regulated in the U.S. under DSHEA is similar, such that a product represented for sale as a dietary supplement may not claim to diagnose, mitigate, treat, cure or prevent a specific disease or class of diseases, although various authorized or qualified health claims may be permitted pending approval from the FDA. Under the NHP Regulations, the opportunity for health claims is better accommodated.
A regulatory approach of requiring any dietary supplement or NHP claiming potential health benefits to meet existing drug legislation could be considered somewhat restrictive, onerous and irrelevant. Realizing the importance for conveying sound, scientific evidence of the benefits of NHPs to consumers, the NHP Regulations provide for various types and categories of product claims based on the credibility, strength and quality of the evidence used to support the claim.
The NHPD defines a claim as "a statement that indicates the intended beneficial effect of a NHP when used in accordance with the labeled dose (i.e., recommended dose), duration of use and route of administration." The permitted types of claims include treatment claims, which relate to the diagnosis, treatment and mitigation or prevention of a disease, disorder, or abnormal physical state or its symptoms in humans. These claims must be supported by the totality of scientific evidence. Risk reduction claims are the second type of permitted claims. Best supported by well-designed observational studies, such as prospective cohort studies, risk reduction claims are based on the relationship between a medicinal ingredient and the reduction in the risk of developing a certain disease; for example, by the alteration of a major risk factor or other contributing factor involved in the development of disease. Another type of permitted claim-structure/function-relates to the effect or support of a NHP ingredient on the structure or anatomical, physiological or mental function in the human body. Examples of structure/function claims include "Maintains healthy gums" or "Reduces blood cholesterol," and where adequately supported by evidence, may include broad statements related to the promotion of overall health.
There are two categories for claims: traditional use claims and non-traditional use claims, each with different requirements for efficacy. Traditional use claims refer to the practices based on the theories or beliefs of indigenous or different cultures used in the maintenance of health or the prevention, diagnosis or treatment of physical and/or mental illness for at least 50 consecutive years. Traditional use claims must be supported by at least two independent references. Non-traditional use claims must be supported by scientific evidence, meaning the requirements are more stringent than for traditional use claims. However, the evidence for non-traditional use claims may be acquired from a wide range of sources, including clinical studies, pharmacopoeias and textbooks, peer-reviewed published articles, pre-clinical studies, reputable regulatory authority reports and expert opinion reports. The strength of evidence for non-traditional claims is graded by level of evidence from human studies, with well-designed randomized, controlled trials bearing the greatest amount of strength, and claims to treat more serious health conditions requiring support by the strongest level of evidence. This system could be compared to the recently published evidence-based ranking system for scientific data for qualified health claims in the U.S. (Guidance: Interim Evidence-Based Ranking System for Scientific Data), which would rank or grade the scientific evidence supporting a claim [i.e., A (High), B (Moderate), C (Low) or D (Extremely Low)] and provide statements to qualify the claim depending on its grade. The level of scientific evidence for a claim for a NHP is similarly graded, although in pre-issuance of a claim. Claims will not be issued for NHPs without sufficient supporting evidence.
Transition Period
Several transitional provisions are outlined in the Regulations that provide for the sale of products that
are already on the market in Canada, either as a food or a drug. The transition period for site licensing and GMPs is two years (January 1, 2006). Products that have already been issued a DIN, but to which the Regulations could be applied have up to six years to register for a NPN (January 1, 2010). Compliance and enforcement for products without DINs will be prioritized according to a risk-based product category priority approach.
Bottom Line
Quintessentially, consumers seek out dietary supplement or natural health products for the purpose of improving their health and overall state of being, and the use of these products is increasing each year. In Canada alone, the market for NHP rose from an estimated (CAD) $1.1-1.8 billion in 2000, to sales of (CAD) $4.3 billion in 2001.
Just as there is no globally accepted term for dietary supplements, neither is there a harmonized set of global regulatory requirements for these products. On an international basis, without a universally accepted regulatory regime, manufacturers of natural therapies have had to comply with varying standards related to safety, efficacy and quality. Regulatory authorities worldwide are realizing the potential positive impact that such products could have on the health of a nation and the frameworks for regulating natural products are shifting to accommodate this change of view. For example, as the U.S. braces for impending changes to its regulations governing dietary supplements, various other jurisdictions are proactively working toward developing comprehensive legislative frameworks for supplement products. Communities such as the EU and Latin America are working toward harmonizing their legislation for dietary supplements and natural health products, although accepted global standards might still be far from realization.
Designed with the goal of providing consumers with products that are safe and efficacious, the NHP Regulations were built on a foundation of sound scientific practice and observation of other regulatory frameworks for such products. Contrary to the previous situation in Canada, the new Regulations provide an even playing field for manufacturers and distributors of NHPs by implementing a unique regulatory category for natural products and developing consistent requirements for the positioning of NHPs for sale in Canada. It has been estimated that the NHP Regulations will affect between 25,000 and 50,000 products on the Canadian market. Although the impact and effectiveness of the Regulations on the state of the industry might not be evidenced for years to come, there is assurance that a framework is now in place in Canada to encourage product safety and quality, while ensuring that consumers have access to efficacious natural health products.NW
About the author: Melody Harwood, B.Sc. (Honors) Toxicology, is a scientific and regulatory consultant with the Food and Nutrition Business Group of Cantox Health Sciences International, Mississauga, Ontario, Canada. She can be reached at 2233 Argentia Road, Suite 308, Mississauga, ON, Canada, L5N 2X7; 905-542-2900; Fax: 905-542-1011; E-mail: mharwood@cantox.com.
