Volume 158, Part B, 2 December 2014, Pages 507–510
Regulation of herbal and traditional medicinal products – European and global strategies (International Symposium TradReg2013)
Abstract
Ethnopharmacological relevance/Introduction
In Canada, all natural health products (NHPs) are regulated by Health Canada (HC) under the Food and Drugs Act and the Natural Health Product Regulations.
All authorized products undergo pre-market assessment for safety,
efficacy and quality and the degree of pre-market oversight varies
depending on the risk of the product.
Overview
In
Canada, over 70,000 products have been authorized for sale and over
2000 sites have been licensed to produce NHPs. In the management of NHPs
on the Canadian market, HC employs a number of active and collaborative
methods to address the most common issues such as contamination,
adulteration and deceptive or misleading advertising practices. HC is
currently evolving its approaches to NHPs to recognize them as part of
the larger group of health products available without a prescription. As
such, the regulatory responsibility for all over-the-counter (OTC)
drugs, including non-prescription drugs and NHPs, has been transferred
to a single federal division.
Conclusion
As
a result of this transition a number of benefits are being realized
with respect to government efficiency, clarity for industry, support for
new innovations and consolidated government interactions with the
Canadian market.
Graphical abstract
Abbreviations
- API, Ayurvedic Pharmacopoeia of India;
- DIN-HM, Homeopathic Medicine Number;
- EMA, European Medicines Agency;
- ESCOP, European Scientific Cooperative on Phytotherapy;
- FDA, Food and Drugs Act;
- GMP, Good Manufacturing Practice;
- HC, Health Canada;
- HMPC, Committee on Herbal Medicinal Products;
- NHPs, Natural health products;
- NNHPD, Natural and Non-prescription Health Products Directorate;
- NHPID, Natural Health Products Ingredients Database;
- NPN, Natural Product Number;
- OTC, Overt-The-Counter;
- PLA, Product Licence Applications;
- PPRC, Pharmacopoeia of the People׳s Republic of China;
- TCM, Traditional Chinese Medicine;
- The Regulations, Natural Health Product Regulations;
- US FDA, United States Food and Drug Administration;
- WHO, World Health Organization
Keywords
- Canada;
- Natural health products;
- Regulation;
- Herbal medicine;
- Monograph
1. Introduction
In
Canada, NHPs are defined to include products such as vitamins and
mineral supplements, homeopathic medicines, herbal therapies,
traditional medicines, amino acids, probiotics and certain personal care
products. In other jurisdictions, due to differences in classification,
many of these products could be considered as “dietary supplements” or
drugs.
This wide group of products is regulated under the Food and Drugs Act (FDA) ( Government of Canda 2013) and the Natural Health Product Regulations (the Regulations) ( Government of Canada 2004)
by the Natural and Non-prescription Health Product Directorate (NNHPD).
The NNHPD is part of the Health Products Food Branch within HC. The
Regulations, which came into force in 2004, cover pre-market product
licensing requirements, site licensing and post-market reporting
requirements. Similar to other health product regulations in Canada, the
Regulations do not apply to the practice of compounding nor to the
practice of medicine, which fall under provincial/territorial
jurisdiction.
Products
authorized for sale in Canada are issued a product license; a Natural
Product Number (NPN) for a NHP or a Homeopathic Medicine Number (DIN-HM)
for a homeopathic product. HC has received over 78,000 license
applications since 2004. Currently, over 70,000 products have been
authorized for sale in Canada, over 2200 companies hold product licenses
for NHPs and over 2000 sites have been licensed.
2. Pre-market review of NHPs
2.1. Product licensing
2.1.1. Classification
Due
to the broad range of products that can be defined as NHPs, scientific
classification decisions are often required to determine the
applicability of the Regulations. All pre-market classification
decisions made by the NNHPD are captured in the Natural Health Products
Ingredients Database (NHPID) (Health Canada 2014c). The NHPID is a repository of scientific terminologies and ingredient information that have been previously evaluated by HC.
2.1.2. Evidence requirements
The
pre-market review of NHPs consists of the review of information to
support the safety, efficacy and quality of the product. HC has
published two guidance documents that outline the evidence requirements
needed to support the safety and efficacy of NHPs, entitled the “Pathway
for Licensing Natural Health Products Making Modern Health Claims” (Health Canada 2012b) and the “Pathway for Licensing Natural Health Products used as Traditional Medicines” (Health Canada 2012c).
Evidence from a range of sources, including clinical studies,
pharmacopoeias, textbooks, peer-reviewed published articles, regulatory
authority reports and traditional references, is considered acceptable
to support the safety and efficacy of a NHP. In general, the level of
evidence (type and amount) required varies depending on the proposed
health claim(s) and the overall risk profile of the product or its
ingredients (Health Canada 2013a). The guidance includes evidence requirements to make basic general health claims as well as more specific health claims.
2.1.3. An example of NHPs in detail: herbal and traditional medicinal products
A
growing number of Canadians rely on herbal and traditional medicines
(e.g. products based on Traditional Herbal Medicine, Traditional Chinese
Medicine (TCM) and Traditional Ayurvedic Medicine). However, the
comprehensiveness of the term “Traditional Medicine” and the wide range
of practices it encompasses, make it difficult to define or describe,
especially in a global context. As per the Regulations, Traditional
Medicine is defined as “medicine based on the sum total of knowledge,
skills and practices based on the theories, beliefs and experiences
indigenous to different cultures, used in the maintenance of health, as
well as in the prevention, diagnosis, improvement or treatment of
physical and mental illness.” This definition has been modified from the
World Health Organization׳s (WHO) “Traditional Medicine Definitions.” (WHO 2014).
Further to this definition, HC has been making efforts to recognize
that traditional medicine evolves over time and industry innovations
have led to an increasing number of combinations of traditional and
herbal products. This has resulted in the considerations of claim
qualifiers, such as “Used in herbal medicine,” based on the combination
of traditional use, scientific evidence and clinical use of NHPs by
practitioners.
2.1.4. NHP monographs
The NNHPD product licensing system allows applicants to reference a monograph (Health Canada 2014b)
in support of the safety and efficacy of a product. A monograph is a
written description of a particular medicinal ingredient or multiple
ingredients with similar claims. Monographs are a comprehensive review
of available information and are based on a totality of evidence
obtained from scientific sources such as clinical trials, reviews,
meta-analysis, and traditional references. Developing the monographs
also involves considering information gathered from other regulatory
agencies such as the WHO׳s herbal monographs, European Medicines
Agency׳s (EMA) Committee on Herbal Medicinal Products׳ (HMPC)
monographs, European Scientific Cooperative on Phytotherapy (ESCOP)
monographs, United States Food and Drug Administration׳s (US FDA) OTC
rulings, and homeopathic pharmacopoeias. The NNHPD also considers
references such as the “Pharmacopoeia of the People׳s Republic of China”
(PPRC) and the “Ayurvedic Pharmacopoeia of India” (API) as stand-alone
references to support traditional uses, as long as the approved
information is consistent with the Regulations.
Monographs
help expedite the authorization process, provide consistency to the
labeling of products on the market, as well as inform industry of the
information that has previously been evaluated by HC. Monographs contain
all of the information required for product licensing including, but
not limited to, the proper and common names, the recommended conditions
of use, and the risk information. Each monograph also provides
information on specifications, including known pharmacopoeial standards
and specific quality requirements for products. In order to reflect
advances in scientific literature, monographs are updated regularly. All
references cited and reviewed in the development of the monograph are
also provided. Monographs are available in both English and French. The
development of monographs, and integrating them into the application
review process, remains a high priority for the NNHPD. To date the NNHPD
has published over 250 monographs, representing hundreds of
ingredients, ranging from traditional herbs to isolates and probiotics.
The herbal medicinal ingredients monographs include herbs used in
Traditional Western Herbal Medicine and herbs used in other traditional
paradigms, such as Ayurvedic Medicine and TCM. The “Traditional Chinese
Medicine Ingredients” monograph, as an example, contains more than 300
TCM ingredients and specifies various conditions under which these could
be used in Canada.
According
to the Regulations, the NNHPD must review a license application within
60 days when the applicant has attested to a monograph listed in the
NNHPD Compendium of Monographs. With the advent of new business
technologies and processes, this timeline is currently being revised to
10 days.
A future step in the
development of monographs includes establishing criteria by which
monographs and similar documents published by other regulatory agencies
can be used to support product authorization in Canada.
2.1.5. Class review based on certainty
The
“Management of Product Licence Applications (PLA) for Natural Health
Products” policy describes a three-class system of product authorization
used to determine the level of pre-market regulatory oversight and the
time in which the NNHPD will conduct its review of the submission. Class
I submissions consist of those products with the highest degree of
certainty in that their benefit and risk profile have been well
established by all available scientific evidence. For this submission
type, applicants can attest to a published monograph in order to obtain
market authorization. Conversely, Class III submissions consist of the
review of products for which there is limited available information.
These include new industry innovations, products carrying claims of a
significant clinical impact, or products containing ingredients with
inherent risks. Class III submissions are required to be supported by
the highest degree of evidence and are associated with the longest
review timelines. In general, Class II submissions are supported in part
by information contained in a monograph as well as by additional
information to support a novel aspect of the product. The new
“Management of Product Licence Applications” policy outlines the
requirements for each class of submission.
2.1.6. Product quality
In
Canada, the quality of NHPs is assured through a balance of pre-market
requirements and site licensing or post-market inspection activities.
There has been a growing recognition of the challenges associated with
marketing high-quality NHPs. These challenges arise, in part, from the
breadth of products captured within the definition of this product
group. The requirements to establish high-quality products vary
drastically between simple food-based ingredient products and highly
refined extracts or sterile products. HC׳s goal is to allow for
flexibility in the regulatory approach, aligning the level of oversight
with the complexity of the product.
The
guidance document, entitled “Quality of Natural Health Products Guide,”
outlines the tools and approaches that can be used to produce
high-quality NHPs, while allowing for flexibility in how those
requirements are met (Health Canada 2013b). Specifically for NHPs, quality requirements focus primarily on characterization, identification, quantification and purity.
Characterization
includes specific standards for chemicals, processed ingredients and
extracts. Specific standards are expected for standardized extracts and
fortified extracts.
For
identification of medicinal plants, product license applicants are
encouraged to use standards such as the WHO׳s Good Agricultural and
Collections Practices Guidelines (WHO 2003). Identity testing is also required on finished products.
Quantification
of NHPs can be achieved through assay or input. Specific methods are
used to assay botanicals, vitamins and minerals, isolates or synthetic
duplicates, live microorganisms and enzymes.
Purity
standards are divided into microbial contaminants, including bacterial
contamination and chemical contaminants. Chemical contamination
standards include, but are not limited to, heavy metals, mycotoxins,
solvent residues, hormones in animal tissues, pesticide residues in
plants, antibiotic residues in bee products and contamination and
oxidative stability in marine oils.
2.2. Site licensing
Prior
to conducting manufacturing, importing, packaging or other activities
in Canada, a site license must be obtained from HC. Applications must
include company details as well as an attestation to Good Manufacturing
Practice (GMP) criteria. In addition, the NNHPD is currently introducing
a proactive inspection program of sites in Canada. A key feature of
this program is an independent on-site audit. NHP manufacturers,
packagers, labelers and importers may elect to undergo an independent
on-site audit to demonstrate compliance with GMP standards (Health Canada 2014a).
Alternatively, the NNHPD may request that a site license applicant
undergo an audit by a HC recognized third party, when critical quality
issues are identified, or when activities involving higher risk product
types are being conducted.
3. Post-market activities
3.1. Background
The
majority of Canadians believe that all products available for purchase
are safe and accurately labeled. However, industry has struggled with
meeting acceptable compliance standards. Compliance within the
marketplace has been improving, but continued examples of non-compliant
products and practices suggest that there is more work to do. For
example, since 2011, 60% of NHP samples analyzed by HC have received
unsatisfactory results and the majority of advertising complaints among
health products are related to NHPs.
Overall,
the post-market issues of greatest concern are characterized as those
involving poor quality or contaminated products, adulterated products
and deceptive or misleading advertising practices. HC employs a number
of active and collaborative methods to aid in mitigating these issues.
3.2. Surveillance
Similar
to many other jurisdictions, HC requires that companies selling their
NHPs in Canada report any adverse effects to HC for analysis.
Post-market surveillance is focused on product safety, quality, and
emerging market trends. Safety issues are assessed with a risk-based
standardized approach. Outcomes of risk assessments could include
product recalls or revised product labeling.
In
general, adverse reactions for NHPs (and all OTC products) are
under-reported and represent just a fraction of the adverse reaction
reports received by HC. To help improve adverse reporting data for this
product group and others, new initiatives, focused on alternative data
sources, have been launched. For example, adverse reports related to
NHPs are now being discovered within poison control centers across the
country. Other sources of data, in addition to easing the reporting
process for the general public, are also being explored.
3.3. Advertising
According to the Food and Drugs Act,
companies are prohibited from product advertising that is false,
misleading or deceptive. Product license holders are responsible for
ensuring that all advertising is within the terms of market
authorization. HC makes use of a complaint-based system as well as
proactive monitoring and media relations to respond to poor advertising
practices.
3.4. Outreach
HC
proactively conducts ongoing communication and outreach activities with
NHP stakeholders, including healthcare professionals, consumers and
industry associations. These outreach initiatives serve many purposes,
such as helping HC inform, monitor and collaborate with industry to
build compliance. In addition, consumers, health professionals, and
government outreach help build demand for compliant products and create a
marketplace that favors good practices and deters non-compliance.
3.5. Compliance and enforcement
HC׳s
approach to compliance and enforcement is progressive in nature. It
consists of a model based on four main principles: 1) high risk
incidents addressed in a timely manner; 2) proactive compliance
monitoring for low risk trends; 3) transparency of compliance status;
and 4) communications to build consumer demand for compliant products.
4. Aligning oversight of products of similar risk
4.1. Background
In
2013, the NNHPD expanded the scope of products over which they have
regulatory authority to include other non-prescription product lines,
including OTC drugs and disinfectants.
This
transition created a single federal division responsible for all OTC
health products; natural or otherwise. As a result of this transition, a
number of benefits are being realized with respect to government
efficiency, clarity for industry, support for new innovations and
consolidated government interactions with the Canadian market.
4.2. Impacts of this alignment
For
Canadians, this alignment is leading to a harmonized approach for what
appears on product labels and improved access to innovative products. It
will also lead to more comprehensive information to support informed
product purchase decisions.
For
the health care system and industry, this will provide a regulator that
aligns with how industry, the practice of medicine, and the market are
organized. It will also lead to consistency and efficiency in decision
making, as well as streamlined and consolidated government interactions.
For
HC, this alignment will provide fewer operational interfaces with other
program areas and clearer accountabilities. It will lead to harmonized
requirements and approaches to product authorizations and labeling, in
addition to a consolidation of expertise in product authorization.
4.3. Consumer health product framework
HC
is working on a vision for Regulatory Modernization. Part of this
vision includes the creation of a Consumer Health Product Framework. The
Framework offers a coordinated, proportional approach to benefit, harm
and uncertainty management of similar products. It distinguishes
oversight applied to natural and non-prescription products from that
applied to prescription products. It modernizes oversight as much as
possible within existing regulatory authorities and offers flexibility
to validate key operational concepts in preparation for later regulatory
change (Health Canada 2012a).
5. Conclusion
Going
forward, the vision of regulating OTC health products including NHPs in
Canada is to ensure that the federal regulatory scheme is designed to
respond to future trends in the field of patient self-care. HC
recognizes that an increasing number of Canadians are using NHPs and
also combining them with other therapies. Canadians have access to
global information about health products and may base their personal
health decisions on this information. The challenge for HC, and our
counterparts in other jurisdictions, will be to design flexible and,
harmonized regulatory approaches to support access to safe, effective
and high-quality products in the future.
References
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