Abbreviations Used in this Article
|DIN||Drug Identification Number|
|GMP||Good Manufacturing Practices|
|HPFB||Health Products and Food Branch|
|NHP||Natural Health Product|
|NHPD||Natural Health Products Directorate|
|NPN||Natural Product Number|
|SOE||Standards of Evidence|
|TPD||Therapeutic Products Directorate|
On June 18, 2003, the Canadian government established a new class of drug products, Natural Health Products (NHPs), when it published the Natural Health Product Regulations (NHP Regulations) in the Canada Gazette Part II.1 This is the final regulatory step that, beginning January 2004, will control all aspects of the commercialization of NHPs, including manufacturing, importation, labeling, and packaging. NHPs include herbal and botanical supplements in dosage form (e.g., pills, tinctures, and even teas, depending on the teas ingredients and claims). A more detailed definition is included below.
Canadas review of the regulatory framework for NHPs began several years ago. The most significant aspect of this review began as a result of the proposed introduction of Establishment Licensing (EL) for drug products, which included many NHPs. EL was tied to the requirement for Good Manufacturing Practices (GMPs) for drugs, which manufacturers of many NHPs (which were and will be regulated as drugs in Canada until January 1, 2004) were required to comply with. Previously, and even today, many NHPs have been and are manufactured to meet food GMPs, despite the ongoing requirement in Canada to meet drug GMPs. Stakeholders, realizing the impact that compliance with drug GMPs would have on the NHP industry, began a coordinated political action campaign. This campaign ultimately led to the governments review of NHPs, completed in November 1998.
This review was conducted by the Standing Committee on Health (the "Committee") of the Federal Parliament. Noting the complexities of the regulation of NHPs the Committee stated, "Although we feel the government has a responsibility to protect public health and safety, this should not be applied in a way that unreasonably denies consumers access to products that they perceive to be necessary for their well being. Thus, a balance must be struck between safety and access."2 Furthermore, the Committee noted, "the framework must allow for more products to be marketed to provide people with that choice."2
The Committee made 53 recommendations in its 1998 report, including creation of a separate regulatory authority responsible for regulation of NHPs. After considering four options, the Committee recommended a new NHP regulatory authority that would report directly to the Assistant Deputy Minister of what is now known as the Health Products and Food Branch (HPFB). This new directorate would be created at the same level within Health Canada as the Therapeutic Products Directorate (TPD), which regulates medical devices and drugs, and the Food Directorate, which regulates food. This new regulatory authority, the Natural Health Products Directorate (NHPD), is to be permanently staffed by individuals with expertise and experience in the field of NHPs, agreeable to both government and NHP stakeholders (e.g., members of the natural health products industry).
The new initiative was affirmed on March 26, 1999, by the Government of Canada and the Minister of Health (Minister), and was greeted by the majority of the NHP stakeholders as a breath of fresh air. A new regulatory authority on par with food, drugs, and devices, staffed with individuals familiar with and accepting of the new category promised a regulatory framework that could increase the number of regulated NHPs authorized to make approved, meaningful health claims. Further, this new system promised to increase acceptance of NHPs by Canadian consumers. In 1998 the proposed new Canadian system caught the attention of the U.S. herb industry and its leaders, particularly because the NHPD was given the same regulatory authority as the directorates that regulate conventional foods and drugs.
The NHP Regulations provide for the following regulatory oversight: (1) a pre-market review and approval process with respect to all aspects of the NHP, including safety, efficacy, claims, and product specifications; (2) a requirement to manufacture, package, and label NHPs in accordance with GMPs that will apply to both domestic and imported NHPs; (3) the requirement to hold a Site License where any regulated activity is carried out with respect to an NHP, including importation; (4) the regulatory oversight of the clinical trial process involving NHPs; and (5) a post-market surveillance program to track potential adverse reactions.
Adverse Reaction Reporting
As part of the post-market surveillance program,3 an NHP product license holder must take certain actions with respect to adverse reactions.4 The Licensee must:
provide a case report for each serious adverse reaction5 to the NHP that occurs in Canada within 15 days of becoming aware of the serious adverse reaction;
provide a case report for each serious unexpected adverse reaction6 to the NHP that occurs inside or outside Canada within 15 days of becoming aware of the serious unexpected adverse reaction;
annually prepare and maintain a summary report that contains a concise and critical analysis of:
º all adverse reactions to the NHP that have occurred inside Canada; and
º all reactions for which a case report is required to be provided within 15 days, that have occurred:
during the previous 12 months; and
at a dose used or tested for the diagnosis, treatment, or prevention of a disease, or for modifying organic functions in humans.
In addition, if the Minister (through the NHPD) has reasonable grounds to believe the NHP is no longer safe to be used under recommended conditions, after reviewing either the case reports or any other safety data, the Minister may request that the NHP license holder provide within 30 days:
a copy of the summary report; or
an interim summary report containing a concise and critical analysis of:
º all adverse reactions to the NHP that have occurred inside Canada; and
º all reactions for which a case report is required to be provided within 15 days, that have occurred;
since the date of the most recent summary report; and
at a dose used or tested for the diagnosis, treatment, or prevention of a disease, or for modifying organic functions in humans.
The foregoing adverse reaction reporting requirements come into effect as soon as the product license applicant (e.g., the manufacturer, importer, distributor, or marketer) receives a product license for the NHP.
This report, together with additional information requested by the Minister (through the NHPD), may be used as justification to stop7 or suspend8 the sale of an NHP. The Minister may direct a licensee, manufacturer, importer, and/or distributor to stop the sale of the NHP. A stop sale directive will only be lifted when the Minister receives information to support the safe use of the NHP. The Minister may direct any of these parties in the distribution chain to stop sale, whether they are the actual licensee or not.
The Minister may also suspend the NHP, but must first give to the Licensee 90 days notice to provide information to support the continued sale of the NHP, unless immediate suspension is necessary to prevent injury to the health of a purchaser or consumer. If a product license is suspended, the Minister must provide the licensee an additional 90 days to respond with more information before the license can be cancelled.
An NHP has a twofold definition,9 based on (1) ingredients; and (2) claims. For a product to be an NHP it must first contain the specific substances set out in Schedule 1 of the NHP Regulations (i.e., plant or plant material, bacteria, fungi [extracts and isolates of same provided there is no change in the molecular structure from that found in nature], certain vitamins, minerals, amino acids, essential fatty acids, probiotics). Synthetic duplicate versions of the foregoing are also included.
In addition to the required ingredients, the NHP must be sold or represented for use in: (a) the diagnosis, treatment, mitigation, or prevention of a disease, disorder, or abnormal physical state or symptoms in humans; (b) restoring or correcting organic functions in humans; or (c) modifying organic functions in humans in a manner that maintains or promotes health. Excluded from the definition of an NHP or from the application of the NHP Regulations are products containing prescription and injectable drugs (including homeopathic injectables), those drugs set out in Schedule C of the Food and Drugs Act (radiopharmaceuticals),10 substances regulated under the Tobacco Act,11 and substances set out in any of Schedules I to V of the Controlled Drugs and Substances Act.12 To clarify, some type of health benefit claim is a mandatory requirement for all NHPs. A manufacturer who previously represented that its product consisted of 500 mg of St. Johns wort without any claim, must say something about the effect of the product. For products with potentially multiple uses (e.g., some single homeopathic preparations), the manufacturer would only include the indications for which it wanted to submit evidence. There is no requirement to claim all potential uses or benefits, even if they are generally known.
In order to sell an NHP, an applicant (i.e., a manufacturer, importer, or distributor) must submit a product license application to the NHPD and receive a product license before the NHP may be sold in Canada. The application for a product license must include sufficient information to support its safety and efficacy.
The type of evidence submitted will determine the types of claims that can be made in association with that NHP (i.e., a structure/function claim, along the lines of those claims being made for dietary supplements in the U.S. under the Dietary Supplement Health and Education Act of 1994), risk-reduction (i.e., the reduction of risk of developing a disease, disorder, or abnormal physical state or its symptoms), or therapeutic claims associated with drugs (i.e., diagnosis, treatment, mitigation, or prevention of a disease, disorder, abnormal physical state or its symptoms). The NHPD is in the process of finalizing the criteria that must be met in order to make a claim, which will be contained in a policy entitled, "Standards of Evidence."
Standards of Evidence
The Standards of Evidence (SOE) will outline the types, strength, quality, and quantity of evidence that will be required by the Minister (through the NHPD) to support the safety and efficacy of an NHP. Based on current documents with regards to the development of the SOE,13 NHPs will be divided into two categories based on ingredients: traditional and non-traditional.
Traditional NHP ingredients are those that are widely used within a cultural context and have been used for 50 years (at least two generations). Previously, non-traditional NHP ingredients were proposed by the NHPD to be divided into three subcategories: (1) generally accepted use (macronutrients), (2) those with previous experience in humans, and (3) limited or no experience in humans (new NHPs). This categorization provided for varying degrees of information that was to be submitted as part of the premarket review process.
It is believed that the NHPD wishes to move away from this categorization to one that divides NHPs into only two categories: traditional and non-traditional (the latter without the subcategories outlined above). In the event that the NHPD adopts this abbreviated approach, additional qualifications will be required in the SOE. These qualifications will be necessary to differentiate between the level of evidence that must be submitted to establish safety and efficacy based on the NHPDs level of familiarity with the non-traditional NHP. The evidential data outlined in the draft SOE ranges from traditional monographs to human clinical trials for new NHPs.
The draft SOE also indicates that the NHPD may use the concept of self-care, self-medication, and responsible self-medication to determine allowable claims for over-the-counter use. This may mean that only the over-the-counter NHPs used in the context of self-treatment may be approvable for sale as an NHP.
Product License Application
As part of the approval process, a product license applicant must provide the proper and common name for each medicinal ingredient,14 its quantity per dosage unit, its potency15 if a representation relating to its potency is to be shown on any labels of an NHP, a description of its source material, and a statement indicating whether it is synthetically manufactured. The product license application must also include a qualitative list of the non-medicinal ingredients that are proposed for the NHP and a statement that indicates the purpose of that ingredient (i.e., an excipient, filler, flowing agent, binder, or coating added for technical and manufacturing purposes). The NHPD proposes to indicate what non-medicinal ingredients may be used without the necessity to provide safety and efficacy data to support their use.
NHPs must be manufactured, packaged, and labeled in accordance with the GMPs outlined within the NHP Regulations, interpreted by a policy to be finalized in November 2003 by the NHPD. In addition, a manufacturer, packager, labeler, or importer must obtain a Site License (SL), which is evidence of GMP compliance (i.e., an SL will not be issued until information is submitted to the NHPD for review to ensure GMP requirements are met).
The product license application must also include the SL numbers for each party conducting any regulated activity with respect to the NHP (i.e., the product applicant is required to provide the SL number for all manufacturers, packagers, and labelers of the NHP). If not available, the information must be provided by the product license holder before sales activity commences. Further, if the NHP is imported, the product license application must include similar information with respect to all foreign sites performing any regulated activities.
Product License Application Review Streams
The product license application review process will be broken down into several streams, based on the type of product license application:
Drug Identification Number (DIN)16 applications originally submitted to the TPD with respect to a drug that will on January 1, 2004, be classed as an NHP and for which the TPD review has not been completed;
abbreviated applications for the conversion of an NHP bearing a DIN;
a product license application submitted in compliance with an NHPD Monograph (for which no evidence needs to be submitted to support safety and efficacy; rather, the applicant attests to compliance with the NHPD Monograph); and
a product license application where there is no NHPD Monograph and evidence must be supplied to support the safety and efficacy of the NHP.
The NHP Regulations require the Minister to complete the review of a product license application within 60 days17 if it is with respect to an NHP where the applicant confirms the NHP complies with an NHPD Monograph. This provision will go into effect July 2004.18 The NHPD has indicated it hopes to release at least 100 monographs prior to January 1, 2004, with another 200 thereafter. The NHPD is developing its own monographs, rather than refer to other established monographs. There is no regulated timeframe for the review of any other product license application.
Of the approximately 50,000 NHPs currently on the Canadian market, only a small number hold a DIN and, thus, could be reviewed quickly since they have already passed the TPDs pre-market review process. It is estimated that more than 10,000 applications will be submitted to the NHPD during 2004 (perhaps during the first several months). In light of this workload and the relative inexperience of the NHPD in reviewing applications, it might take more than a year to obtain approval and a Natural Product Number (NPN).
The NHP Regulations outline specific labeling requirements for NHPs and include, by reference, certain labeling requirements for drugs from the Food and Drug Regulations. Some of the labeling requirements include recommended conditions of use, the common and proper name of each medicinal ingredient, a listing of the non-medicinal ingredients, storage conditions, a description of the source material of a medicinal ingredient, a lot number, and expiry (expiration) date.
While the NHP Regulations will become effective January 2004, a transition period will permit staged compliance over six years for products bearing a DIN and offered for sale prior to January 1, 2004. There is a two-year transitional period for GMP compliance and to obtain a Site License; four years to obtain a product license and comply with labelling requirements; and, finally, six years to convert existing drug products that already have a DIN.
These transition provisions have been revised from the first draft of the NHP Regulations and appear to only permit the sale of an NHP that is not yet in compliance with NHP Regulations during the relevant transition period, provided the NHP has been issued a DIN. This is not the case for many products presently in the Canadian market.
It is believed that the NHPD intends to prioritize enforcement of the NHP Regulations according to the potential level of risk to consumers of non-compliant NHPs. The NHPD intends to review all non-compliant NHPs to bring them into compliance according to this risk-management approach over the four-year transition period for product licensing.
To date, this approach has been referred to by the NHPD in oral discussions in response to inquiries as to the content of a yet-to-be-released Compliance and Enforcement Policy. Without the inclusion of very clear language as to the fundamentals of this approach, as well as the criteria upon which NHPs will be reviewed to bring them into compliance, those involved with the sale of non-compliant NHPs will have little defense to the enforcement of the NHP Regulations by the HPFB Inspectorate, a separate, and equal, entity within Health Canada. Hopefully, this issue will be answered early this fall with the release, in draft form at least, of a Compliance and Enforcement Policy.
Public Education and Research
The NHPD has indicated that by November 2003 it intends to launch a public awareness campaign to inform both stakeholders and consumers about the NHP Regulations and their impact. The Regulatory Impact Analysis Statement notes that the NHPD will work with the industry to educate and inform the industry on the new requirements.
As a result of the 1998 Committee recommendations, several
federal governmental research bodies were asked to encourage research immediately
with respect to NHPs. In response, the NHPD has been developing research priorities
and strategies to ensure effective use of research dollars. In addition, Health
Canada has committed Can$5 million over five years to create the NHP Research
Program. The complete NHP Regulations can be viewed at
Joel B. Taller is a partner in the Ottawa office of Gowling Lafleur Henderson LLP, where he has worked exclusively in the area of product regulation since 1983, prior to his call to the Ontario Bar in 1985. He received his law degree and MBA from the University of Ottawa, and a BSc (Honours) in physiology and pharmacology from the University of Western Ontario. He specializes in regulatory issues affecting NHP, foods, drugs, devices, and cosmetics.
1. Natural Health Products Regulations, S.O.R.[Statutory Orders and Regulations]/2003-196.
2. Canada, Standing Committee on Health. Natural Health Products: A New Vision. November 1998:69.
3. S.O.R./2003-196, S.24
4. "Adverse reaction" means a noxious and unintended response to a natural health product that occurs at any dose used or is tested for the diagnosis, treatment or prevention of a disease or for modifying an organic function. S.O.R./2003-196, S.1(1).
5. "Serious adverse reaction" means a noxious and unintended response to a natural health product that occurs at any dose and that requires in-patient hospitalization or a prolongation of existing hospitalization, that causes congenital malformation, that results in persistent or significant disability or incapacity, that is life threatening, or that results in death. S.O.R./2003-196, S.1(1).
6. "Serious unexpected adverse reaction" means a serious adverse reaction that is not identified in nature, severity, or frequency in the risk information set out on the label of the natural health product. S.O.R./2003-196, S.1(1).
7. S.O.R./2003-196, S.16 and 17.
8. S.O.R./2003-196, S.18 to S.21.
9. S.O.R./2003-196, S.1.
10. Food and Drugs Act. RSC 1985, c. S-27, Sch.C.
11. Tobacco Act. S.C. 1997, c. 13.
12. Controlled Drugs and Substances Act. SC 1996, G-17, Sch. 1-V.
14. Proper name means one of the following: (a) if the ingredient is a vitamin, the name of the vitamin set out in item 3 of Schedule 1; (b) if the ingredient is a plant or plant material, an alga, a bacterium, a fungus, a non-human animal material, or a probiotic, the Latin nomenclature of its genus, and if any, its specific epithet; and (c) if the ingredient is other than as described in paragraphs (a) and (b) above, the chemical name of the ingredient.
15. Potency refers to the amount per dose form of a particular component which has been standardized, which further characterizes the quantity of the medicinal ingredient (i.e., St. Johns wort standardized to 0.3% hypericin); contrast this with quantity (i.e., 1,200 mg of St. Johns wort).
16. A DIN, or Drug Identification Number, is evidence that the drug has been reviewed by Health Canada and permitted to be sold. It is the number assigned following a pre-market review of a drug identification number application submitted to the TPD. A drug cannot be sold without first going through a pre-market review and having been assigned a DIN which must be included on the label.
17. S.O.R./2003-196, S.6.
18. S.O.R./2003-196, S.116.