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Regulatory information resources for nutraceuticals and functional
foods: resource guide
Veling, Mary
https://publications-cnrc.canada.ca/fra/droits
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Re gula t ory I nform a t ion
Re sourc e s for N ut ra c e ut ic a ls
a nd Func t iona l Foods:
Re sourc e Guide
Prepared for
NRC-IRAP, Atlantic & Nunavut region
Prepared by
Mary Veling, Information Specialist, NRC-CISTI
In consultation with
Valerie Baker, Technical Business Analyst, NRC-IRAP
Number
11-5399
Date
February 2012 (
replaces August 2011 version)
NRC-CISTI employees make every effort to obtain information from reliable sources.
However, we assume no responsibility or liability for any decisions based upon the information presented.
Contents
1 Introduction ... 4
2 Nutraceuticals and Functional Foods ... 5
2.1 Canada ... 5
2.1.1 Natural Health Products ... 5
2.1.2 Novel Foods ... 7 2.2 United States ... 7 2.2.1 Dietary supplements ... 7 2.3 European Community ... 9 2.3.1 Food Supplements ... 9 2.3.2 Novel Foods ... 10 3 Drugs / Pharmaceuticals ... 10 3.1 Canada ... 10 3.2 United States ... 11 3.3 European Community ... 12 3.3.1 Medicinal Products ... 12
3.3.2 Herbal Medicinal Products ... 12
3.3.3 Orphan Medicinal Product ... 13
3.3.4 Paediatric Medicine ... 14
4 Biologics and Subsequent Entry Biologics (Biosimilars) ... 14
4.1 Canada ... 14 4.2 United States ... 15 4.3 European Community ... 16 5 Clinical Trials ... 16 5.1 Canada ... 16 5.2 United States ... 16 5.3 European Community ... 16
5.4 International Clinical Trial Registries ... 17
6 Veterinary Drugs, Biologics and Feeds ... 17
6.1.1 Veterinary Biologics ... 18
6.1.2 Novel Animal Feeds ... 18
6.2 United States ... 18
6.2.1 Veterinary Biologics ... 19
6.2.2 Animal Feeds ... 19
6.3 European Community ... 19
Note:
- Unless otherwise noted all resources in sections for Canada are from Health Canada.
- Canadian consolidated Acts and regulations are sourced from the Justice Laws Website at the Department of Justice.
- The U.S. Code of Federal Regulations (CFR) and other US regulations are sourced from FDsys, GPO’s Federal Digital System which replaces GPO Access. Access is also available through e-CFR but it is not an official legal edition of CFR.
- CFR is an annual publication that codifies the general and permanent rules published in the Federal Register by the departments and agencies of the Federal Government. It is divided into 50 titles that represent broad areas subject to Federal regulation. C.F.R. 9 revised January 1 and C.F.R 21 revised as of April 1 are the two primary regulations referred to in this document. To find the CFR titles on FDsys it is best to use the “Retrieve by Citation”, if you know the title and part or section numbers. Option is listed under “Advanced Search” on FDsys home page search box.
- European Community (EC) regulations are covered, not the individual Member State regulations. Community legislation referred to in this document includes both regulations and directives. Regulations are laws that take effect in all Member States, while directives are binding on the Member States to achieve the result through their own legal framework.
- EC regulations and directives are sourced from EUR-Lex, the European Union law site. For this guide the permanent link to the Directive or Regulation was used. This will retrieve the main record with the record history and text of the legislation. The record includes links to any amendments should include a link to the latest “consolidated” version in PDF, if available.
1 Introduction
This resource guide was developed as a tool to facilitate easy access to regulatory information for nutraceutical and functional food product development and marketing. It provides links to selected Canadian, U.S. and European information resources for the laws and regulations that pertain to nutraceuticals and related products. These information resources also include links to guidance documents and databases or listings for approved products and clinical trials. Other subject areas such as pharmaceuticals, biologics and veterinary drugs are covered where they relate to nutraceuticals and functional foods.
There is no global uniformity for regulating nutraceuticals. Approaches vary by country and Canada, the U.S. and Europe do not have regulations that specifically refer to “nutraceuticals” or “functional foods”. Instead regulations refer to such categories as “natural health products”, “dietary/food
supplements” or “novel foods”. Definitions vary and deciding where a product fits is often difficult and dependent on national perceptions.
Nutraceuticals sits between food and drugs, or pharmaceuticals, and depending on the claims made and the country’s legislation the “nutraceutical” may fall within either drug or food regulations.
Regulation of nutraceuticals and functional foods is becoming more stringent. This means that companies working in these areas will need to pay special attention to the regulations that affect their products and watch for any new or revised regulations. Complying with regulations is often a complex effort that may require advice from regulatory specialists.
Two sources for monitoring the regulatory environment are the Regulatory and Legislation section of
New Hope 3601, and Nutraceuticals World. For the second source you need to search the site for regulation related items. The site's search only allows for a single term or a phrase. If you need more precise information than it's best to use Google's site search capability, for example: china regulations OR regulatory site:www.nutraceuticalsworld.com.
1 New Hope 360 is a digital marketplace providing information from various sources including Functional Ingredients
2 Nutraceuticals and Functional Foods
2.1 Canada
Although there are no standard definitions for nutraceuticals and functional foods, Health Canada proposes the following definitions:
A nutraceutical is a product isolated or purified from foods that is generally sold in medicinal forms not usually associated with food. A nutraceutical is demonstrated to have a physiological benefit or provide protection against chronic disease.
A functional food is similar in appearance to, or may be, a conventional food, is consumed as part of a usual diet, and is demonstrated to have physiological benefits and/or reduce the risk of chronic disease beyond basic nutritional functions.
- According to Health Canada (Section 3.1) there are no regulations dealing specifically with nutraceuticals or functional foods. All foods and drugs fall under the provisions of the Food and Drugs Act (R.S., 1985, c. F-27) and the Food and Drug Regulations (C.R.C., c.870). They may be considered a drug if the claims made by the manufacturer meet the definition of a drug. If a drug, then they are generally regulated as a subset of drugs under the Natural Health Products Regulations (SOR/2003-196).
- Additional information on Functional Foods and Nutraceuticals is available from Agriculture and Agri-Food Canada.
2.1.1 Natural Health Products
Health Canada defines “natural health products” (NHPs) as • Vitamins and minerals
• Herbal remedies
• Homeopathic medicines
• Traditional medicines such as traditional Chinese medicines • Probiotics, and
• Other products like amino acids and essential fatty acids
“Natural health product” as defined in the Natural Health Products Regulations (SOR/2003-196):
“natural health product” means a substance set out in Schedule 1 or a combination of substances in which all the medicinal ingredients are substances set out in Schedule 1, a homeopathic medicine or a traditional medicine, that is manufactured, sold or represented for use in
(a) the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state or its symptoms in humans;
(b) restoring or correcting organic functions in humans; or
(c) modifying organic functions in humans, such as modifying those functions in a manner that maintains or promotes health.
Substance components set out in Schedule 1 include plants, algae, bacteria, fungi, animal products (human or otherwise), and homeopathic medicines, including probiotics, amino or
fatty acids, vitamins, and minerals. NHPs may also comprise extracts, isolates, or synthetic versions of the same substances.
Natural health products are considered to be a subset of "drugs" under the current Food and Drugs Act.
- Regulating authority for NHPs is the Natural Health Products Directorate (HHPD), Health Products and Food Branch, Health Canada.
- Natural Health Products – main page.
- The Natural Health Products Regulations (SOR/2003-196) (Canada Dept. of Justice) contains requirements for manufacturing, packaging, labelling, storing, importing, distributing and selling natural health products.
- Overview of the Natural Health Products Regulations Guidance Document can be used to determine whether a product is governed by the Natural Health Products Regulations. - Classification of Products at the Food-Natural Health Product Interface: Products in Food
Formats, Natural Health Products Directorate and Food Directorate, Health Canada, June 10, 2010. – Food or natural health product? This guidance document can be used to help determine if a product in a food format is a natural health product.
- About Natural Health Product Regulation in Canada – provides a more concise overview of the topic, with links to key resources.
- Health claims for natural health products, updated November 2010. - Natural Health Products guidance documents.
- Good Manufacturing Practices Guidance Document, Natural Health Products Directorate, Health Canada, August 2006, version 2.0.
- NHPs Labelling Guidance Document is intended to help product license applicants interpret the labelling and packaging requirements specified in Section 5 of the Natural Health Products Regulations when selling a natural health product within Canada. - Clinical Trials for Natural Health Products guidance document.
- Consumer Advertising Guidelines for Marketed Health Products (for Nonperscription
Drugs including Natural Health Products guidance document.
- Licensed Natural Health Products Database – searchable database of natural health products that have been licensed for sale in Canada. Each product profile includes a list of medicinal and non-medicinal ingredients.
- Natural Health Products Ingredients Database (NHPID) – searchable database of acceptable medicinal and non-medicinal ingredients used in Natural Health Products. - Traditional Herbal Medicines guidance documents.
2.1.2 Novel Foods
“Novel foods” are described by Health Canada as:
- Foods resulting from a process not previously used for food;
- Products that do not have a history of safe use as a food (that is, products that have never been used as food); or
- Foods that have been modified by genetic manipulation, also known as genetically modified foods, GM foods, genetically engineered foods or biotechnology-derived foods.
Nutraceuticals or functional foods may, every now and then, fit within this definition.
- Genetically modified (GM) food and novel foods are regulated by Health Canada under Division 28 of the Food and Drug Regulations (C.R.C., c. 870).
- Novel foods guidance documents.
- Guidelines for the Safety Assessment of Novel Foods, Food Directorate, Health Products and Food Branch, Health Canada, June 2006.
- Frequently Asked Questions - Biotechnology and Genetically Modified Foods (and other novel foods, including labelling).
- Novel Food Decisions – Approved Products – a list of approved GM foods and novel foods.
2.2 United States
In the US herbs and botanicals are regulated under dietary supplements.
2.2.1 Dietary supplements
The Dietary Supplement Health and Education Act of 1994 defines a “dietary supplement” as a product taken by mouth that contains a dietary ingredient that supplements the diet. The dietary ingredients may include vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandulars, and metabolites. Whether the dietary supplement is in powder or liquid or other form, the DSHEA places dietary supplements in a special category under the general umbrella of "foods," not drugs, and requires that every supplement be labelled a dietary supplement.
- Dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) under the under the Dietary Supplement Health and Education Act of 1994 (DSHEA).
- Regulations for dietary supplements are codified in the Code of Federal Regulations (Title 21) Food and Drugs. These are in various sections and can be found by searching for dietary supplements. The regulations pertain mainly to labelling.
- Dietary supplements – Industry Information and Regulations, principal regulations that govern the labelling and claims for dietary supplements.
- Dietary Supplements – Regulations & Laws, including Current Good Manufacturing Practices (CGMPs).
- Dietary Supplement Labeling – provides requirements and guidance for labelling and
making claims for supplements (e.g. qualified and structure/function claims).
- Dietary Supplements Labels Database of the National Library of Medicine provides information about label ingredients in more than 6,000 selected brands of dietary supplements.
- Guidance for Industry: Dietary Supplement Labeling Guide, Center for Food Safety and Applied Nutrition (CFSAN), FDA, April 2005.
- Guidance for Industry: Questions and Answers Regarding the Labeling of Dietary
Supplements as Required by the Dietary Supplement and Nonprescription Drug Consumer Protection Act, FDA, December 2007; Revised December 2008 and September 2009 - Guide to Nutrition Labeling and Education Act (NLEA) Requirements, FDA, August 1994. - Summary of qualified health claims – for food and dietary supplements.
- Health Claims Meeting Significant Scientific Agreement (SSA) – provides guidance documents and listing for approved food and dietary supplement health claims.
- If a botanical dietary supplement is intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in humans then it is investigated as a new drug and subject to drug regulations, see Frequently Asked Questions on Botanical Drug Product Development.
- Safety of dietary supplements is the responsibility of the manufacturer. Once a product is
marketed the FDA can only restrict or remove a product from the marketplace by showing that a dietary supplement is unsafe. See Guidance for Industry: Questions and Answers Regarding Adverse Event Reporting and Recordkeeping for Dietary Supplements as Required by the Dietary Supplement and Nonprescription Drug Consumer Protection Act. FDA, October 2007; Revised June 2009.
- Some food ingredients are classified as "generally recognized as safe" or "GRAS”.
Information on GRAS at FDA.
- GRAS Notice Inventory – inventory of GRAS notices filed since 1998. Can search by substance or browse listing. Data includes the basic GRAS records and FDA’s letter describing there response, if no longer pending.
- GRAS Substances (SCOGS) Database (see link to “Launch Database” at the bottom of the page) - provides opinions and conclusions from 115 SCOGS 2 reports published between 1972-1980 on the safety of over 370 Generally Recognized As Safe (GRAS) food substances.
- Guidance for Industry: Frequently Asked Questions about GRAS.
2
2.3 European Community
In the European Community, nutraceuticals are at the boundary between drugs and food.
- Nutraceutical products with specific therapeutic claims are considered drugs – see Section 3.3 in this document.
- Nutraceutical products with non-therapeutic claims are regulated independently by member states, most often falling under food regulations and standards.
- The EU legislation does not specifically reference nutraceuticals or functional foods. Instead there is EU legislation on food supplements and novel foods.
- Herbal medicinal products are covered in Section 3.3.2 in this document. - Non-medicinal herbal products can be regulated as foods or food supplements.
2.3.1 Food Supplements
A “food supplement” is defined in Directive 2002/46/EC3 as:
(a) ‘food supplements’ means foodstuffs the purpose of which is to supplement the normal diet and which are concentrated sources of nutrients or other substances with a nutritional or physiological effect, alone or in combination, marketed in dose form, namely forms such as capsules, pastilles, tablets, pills and other similar forms, sachets of powder, ampoules of liquids, drop dispensing bottles, and other similar forms of liquids and powders designed to be taken in measured small unit quantities;
(b) ‘nutrients’ means the following substances: (i) vitamins,
(ii) minerals.
- According to the definition, food supplements are subject to Regulations that cover
foodstuffs except where specifically provided for in the food supplements legislation.
To fall under the food supplements legislation, Directive 2002/46/EC, the product must be in concentrated form and in measured small unit quantities. Otherwise, the food law regulation,
Regulation (EC) No 178/20024 would apply.
- Nutrition and health claims are regulated under Regulation (EC) No 1924/2006.5 The regulation allows for three functional claims: “general function” claims are covered in Article 13.1; “new function” claims are covered in Article 13.5; and claims on disease risk reduction
and claims referring to children's development and health are covered in Article 14. - Health claims must be submitted to the European Food Safety Authority (EFSA) for
evaluation – Guidance for applicants on health claims.
3
Directive 2002/46/EC of the European Parliament and of the Council of 10 June 2002 on the approximation of the laws of the Member States relating to food supplements
4
Regulation (EC) No 178/2002 of the European Parliament and of the Council of 28 January 2002 laying down the general principles and requirements of food law, establishing the European Food Safety Authority and laying down procedures in matters of food safety
5 Regulation (EC) No 1924/2006 of the European Parliament and of the Council of 20 December 2006 on nutrition and health
- Health claims assessed by the European Food Safety Authority (EFSA) for which the authorisation procedure is finished may be found in the EU Register on nutrition and health claims made on food. Includes authorised and rejected health claims.
2.3.2 Novel Foods
“Novel foods” are defined in Regulation (EC) No 258/976 as:
Novel foods are foods and food ingredients that have not been used for human consumption to a significant degree within the Community before 15 May 1997 and which fall under various categories.
- Rules for safety assessment of novel foods and novel food ingredients are covered by
Regulation (EC) No 258/97.
- Novel Foods and novel food ingredients – main page
- Novel Foods and novel food ingredients – Review of Regulation (EC) 258/97. - List of Commission Decisions authorising the placing on the market of novel food. - The Novel Food Catalogue is a listing of foods and food ingredients that has been
collected since the “Novel Food Regulation” (Regulation 258/97/EC) entered into force is in three parts. The document also may contain information on the history of use by Member States of food supplements and ingredients used exclusively in food supplements. See link to “Novel food catalogue” at the bottom of the page.
3 Drugs / Pharmaceuticals
3.1 Canada
Drugs as defined in the Food and Drugs Act (R.S., 1985, c. F-27), Canada Dept. of Justice: “drug” includes any substance or mixture of substances manufactured, sold or represented for use in
(a) the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state, or its symptoms, in human beings or animals,
(b) restoring, correcting or modifying organic functions in human beings or animals, or
(c) disinfection in premises in which food is manufactured, prepared or kept;
- Food and Drug Regulations (C.R.C., c.870), Canada Dept. of Justice.
- Guidance Documents for drug products provide interpretation of policies and governing statues and regulations.
- Good Manufacturing Practices (GMP) Guidelines - 2009 Edition (GUI-0001). The guidelines apply to pharmaceutical, radiopharmaceutical, biological, and veterinary drugs.
6 Regulation (EC) No 258/97 of the European Parliament and of the Council of 27 January 1997 concerning novel foods and
- Drug Product Database – product specific information on drugs approved for use in Canada; includes human pharmaceutical and biological drugs, veterinary drugs and disinfectant products.
3.2 United States
Drug is defined in section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act as:
The term "drug" means (A) articles recognized in the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of any article specified in clause (A), (B), or (C).
- The U.S. Food and Drug Administration (FDA) regulates all drugs through the Federal Food, Drug, and Cosmetic Act and its amendments.
- Drug regulations are codified in the Code of Federal Regulations (Title 21) Food and Drugs. Regulations specific to new drug applications can be found in Part 310 of the C.F.R. 21. - Within the FDA, the Center for Drug Evaluation and Research (CDER) is responsible for
drug products.
- Form and submission requirements for new drugs – Investigational New Drugs (IND) and New Drug Applications (NDA) stages, as well as forms for orphan drugs and generic drug products.
- Good manufacturing practice (GMP) documents for drugs. - CDER and other FDA drug guidance documents.
- Guidance for Industry: Botanical Drug Products, CDER, June 2004. (PDF 347KB / 52 pages)
- Frequently Asked Questions on Botanical Drug Product Development.
- FDA Basics for Industry a new website launched Jan 2011 by the FDA to help companies and others with basic information on the regulatory process. This site pulls together
information from the regular FDA site, making it easier for industry to locate what they need. - Drugs @ FDA – database of approved brand name and generic prescription and
over-the-counter human drugs and biological therapeutic products. Records provide brief product information such as active ingredients, company name, approval date and approval documents.
- Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations – prescription, over-the-counter and discontinued drug products database. Records provide brief product information.
3.3 European Community
3.3.1 Medicinal Products
“Medicinal product” is defined in Directive 2001/83/EC 7 as:
(a) Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or
(b) any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.
The substance may be human, animal, vegetable or chemical.
- The European Medicines Agency (EMA) is responsible for the evaluation of human and veterinary medicines developed by pharmaceutical companies for use in the European Union. The scientific evaluations of human medicines are carried out by the Committee for Medicinal Products for Human Use (CHMP).
- EU legislation and procedures for the regulation of medicinal products for human use – see Volumes 1 and 2-4 and 9-10 of The Rules Governing Medicinal Products in the European Union.
- The primary EU legislation is Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency.
- Human medicines: Regulatory and procedural guidance index.
- European Public Assessment Reports (EPARs) for human medicines that have been granted a Community marketing authorisation by the European Commission. Search options for this database include browse by therapeutic area. Records provide extensive
information.
3.3.2 Herbal Medicinal Products
Directive 2004/24/EC8 provides definitions for herbal medicinal products, herbal preparations and herbal substances.
- Herbal medicinal product: Any medicinal product, exclusively containing as active
ingredients one or more herbal substances or one or more herbal preparations, or one or more such herbal substances in combination with one or more such herbal preparations. - Herbal substances: All mainly whole, fragmented or cut plants, plant parts, algae, fungi,
lichen in an unprocessed, usually dried, form, but sometimes fresh. Certain exudates that have not been subjected to a specific treatment are also considered to be herbal
substances. Herbal substances are precisely defined by the plant part used and the
7
Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use
8 Directive 2004/24/EC of the European Parliament and of the Council of 31 March 2004 amending, as regards traditional
botanical name according to the binomial system (genus, species, variety and author).
- Herbal preparations: Preparations obtained by subjecting herbal substances to treatments such as extraction, distillation, expression, fractionation, purification, concentration or fermentation. These include comminuted or powdered herbal substances, tinctures, extracts, essential oils, expressed juices and processed exudates.
- EMA’s Committee on Herbal Medicinal Products (HMPC) prepares the Community list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products, and establishes Community herbal monographs.
- Herbal medicinal products: Regulatory and procedural guidance documents – see specifically: Directive 2004/24/EC of the European Parliament and of the Council of 31 March 2004 amending, as regards traditional herbal medicinal products, Directive 2001/83/EC on the Community code relating to medicinal products for human use.
- Additional information can be found on the EMA’s main page for Herbal Medicinal Products. - Database of herbal substances designated for assessment by the European Medicines
Agency's Committee on Herbal Medicinal Products (HMPC). Records with final status can include key documents such as herbal monographs and assessment reports.
- Non-medicinal herbal products are regulated as foods or food supplements – see Section 2.3.1 in this document.
3.3.3 Orphan Medicinal Product
“Orphan medicinal product” is defined in Regulation (EC) No 141/2000 9 as:
A medicinal product shall be designated as an orphan medicinal product if its sponsor can establish:
that it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting not more than five in 10 thousand persons in the Community when the application is made, or
that it is intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition in the Community and that without incentives it is unlikely that the marketing of the medicinal product in the Community would generate sufficient return to justify the necessary investment; and
that there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorised in the Community or, if such method exists, that the medicinal product will be of significant benefit to those affected by that condition.
- Orphans: Regulatory and procedural guidance documents – see specifically Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products.
9
Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products
- EMA’s Committee for Orphan Medicinal Products (COMP) is responsible for reviewing applications from persons or companies seeking 'orphan medicinal product designation' for products they intend to develop for the diagnosis, prevention or treatment of life-threatening or very serious conditions.
3.3.4 Paediatric Medicine
“Paediatric medicine” is defined in Regulation (EC) No 1901/200610 as:
'medicinal product authorised for a paediatric indication’ means a medicinal product which is authorised for use in part or all of the paediatric population and in respect of which the details of the authorised indication are specified in the summary of the product characteristics drawn up in accordance with Article 11 of Directive 2001/83/EC.
- Paediatric medicines: EU Paediatric Regulation.
- The main responsibility of the EMA’s Paediatric Committee (PDCO) is to assess the content of paediatric investigation plans and adopt opinions on them in accordance with Regulation (EC) 1901/2006 as amended.
4 Biologics and Subsequent Entry Biologics (Biosimilars)
4.1 Canada
“Biologics” are derived from natural sources – humans, animals or microorganisms. They include a wide range of products such as vaccines, blood or blood components, cytokines, monoclonal antibodies, proteins, and gene therapy products. They are considered a subset of drugs, but have a slightly different regulatory approach. This is due, in large part, to their molecular complexity and their sensitivity to changes in storage or the manufacturing process --- as a result, much more emphasis is placed on the manufacturing process and on quality control. –Health Canada
A “Subsequent Entry Biologic” is a biologic drug that enters the market subsequent to a version previously authorized in Canada, and with demonstrated similarity to a reference biologic drug. A subsequent entry biologic relies in part on prior information regarding safety and efficacy that is deemed relevant due to the demonstration of similarity to the reference biologic drug and which influences the amount and type of original data required. –Health Canada
- Regulatory responsibility for biologics is with Health Canada’s Biologics and Genetic Therapies Directorate.
- Regulatory initiatives for Biologics, Radiopharmaceuticals and Genetic Therapies. - Vaccine regulation regulatory initiatives.
10
Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004
- Blood and Blood Components regulatory initiatives.
- Cells, Tissues, and Organs for Transplantation and Assisted Human Reproduction
regulatory initiatives.
- Fact Sheet for Subsequent Entry Biologics in Canada.
- Guidance documents for Subsequent Entry Biologics (SEBs).
- Annex 2 to the Current Edition of the Good Manufacturing Practices Guidelines Schedule D Drugs (Biological Drugs) (GUI-0027) – provides GMP for biological drugs.
4.2 United States
“Biological products” include a wide range of products such as allergenics, blood and blood components, gene therapy, human tissues and cellular products, vaccines, and xenotransplantation products. –FDA
“Follow-on protein products” refers to proteins and peptides that are intended to be sufficiently similar to a product already approved under the Federal Food, Drug, and Cosmetic Act or licensed under the Public Health Service Act to permit the applicant to rely on certain existing scientific knowledge about the safety and effectiveness of the approved protein product. –FDA. This is equivalent to Canada’s subsequent entry biologics or the EU’s biosimilars.
- The Center for Biologics Evaluation and Research (CBER) is the Center within FDA that regulates biological products for human use, under various laws, including the Public Health Service Act and the Federal Food, Drug, and Cosmetic Act and its amendments.
- Regulations specific to biological products can be found starting in Part 600 of the Code of
Federal Regulations (Title 21) Food and Drugs. C.F.R.21 defines biological products as any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment or cure of diseases or injuries of man.
- Biologics Guidance, Compliance & Regulatory Information.
- Follow-on protein products, compilation of presentations, and public comments on scientific and regulatory issues related to the development of follow-on protein products.
- Human Cell and Tissue Establishment Registration (HCTERS) Public Query Application –
database of registered, inactive and pre-registered human cells, tissue, and cellular and
tissue-based product establishments.
- Stay informed on biologics by subscribing to biologics mailing lists. This listing for FDA
4.3 European Community
“Advanced therapy medicinal product” is defined in Regulation (EC) No 1394/2007 11 as any tissue engineered products, gene therapy medicinal products, or somatic cell medicinal products for human use.
- The European Medicines Agency’s (EMA) Committee for Advanced Therapies (CAT) is responsible for the scientific evaluation of ATMP marketing authorisation applications
submitted by pharmaceutical companies. CAT prepares a draft opinion which is submitted to EMA’s Committee for Medicinal Products for Human Use (CHMP), the committee
responsible for human medicines at the Agency.
- Advanced therapies: Regulatory and procedural guidance documents.
- Scientific guidelines on gene therapy and on cell therapy and tissue engineering are
available to help applicants prepare marketing-authorisation for advanced therapy medicinal products.
5 Clinical Trials
5.1 Canada
- Clinical trials guidance documents – Health Canada. - Clinical Trials Manual.
- Clinical Trials for Natural Health Products – guidance document.
5.2 United States
- Running clinical trials: Regulations.
- Running clinical trials: Guidance documents.
- Running clinical trials: Draft regulations and guidances.
5.3 European Community
- EudraCT is a database of information on the content, commencement and termination of all clinical trials in the European Union (from 1 May 2004 onwards). It was established in accordance with Directive 2001/20/EC, and is managed by the European Medicines Agency. – This is not a searchable database. It functions as a system to obtain a EudraCT number and submit clinical trial application forms.
- Clinical trials guidelines – volume 10 of The Rules Governing Medicinal Products in the European Union.
11 Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy
5.4 International Clinical Trial Registries
- NIH ClinicalTrials.gov Register of federally and privately supported clinical trials conducted in the United States and around the world.
- Current Controlled Trials search and register clinical trials, can also search across multiple clinical trial registers (ISRCTN registers and ClinicalTrials.gov.
- International Clinical Trials Registry Platform (ICTRP) – World Health Organization; includes data sets from ClinicalTrials.gov, ISRCTN and other national registries like the Australia New Zealand Clinical Trials Registry.
6 Veterinary Drugs, Biologics and Feeds
6.1 Canada
“Veterinary drugs” are defined in the Food and Drugs Act and fall under the general definition of a drug – see Section 5.1 in this document.
Canadian Food Inspection Agency (CFIA) describes a “veterinary biologic” as: - a helminth, protozoa or micro-organism,
- a substance or mixture of substances derived from animals, helminths, protozoa or micro-organisms, or
- a substance of synthetic origin
that is manufactured, sold or represented for use in restoring, correcting or modifying organic functions in animals or for use in the diagnosis, treatment, mitigation or prevention of a disease, disorder, abnormal physical state, or the symptoms thereof, in animals. Veterinary biologics include vaccines, bacterins, bacterin-toxoids, immunoglobulin products, diagnostics kits, and any veterinary biologic derived through biotechnology. (definition based on the Health of Animals Act (1990, c. 21))
CFIA describes “novel feeds” as feeds composed of or derived from microorganisms, plants or animal sources that:
(a) are not approved as livestock feed in Canada (not listed in Schedule IV or V of the Feeds Regulations)
(b)and/or contain a novel trait
Novel feeds include microbial products (e.g. forage inoculants, fermentation products) plants with novel traits, and plants with no history of use as feed, and products/by-products of biotechnology-derived animals. (definition based on the Feeds Regulations, 1983 (SOR/83-593))
- The Veterinary Drugs Directorate of Health Canada evaluates and monitors the safety and efficacy of veterinary drugs in Canada under the Food and Drugs Act (R.S., 1985, c. F-27)
and the Food and Drug Regulations (C.R.C., c.870).
- Veterinary drugs: Guidance documents and veterinary drug approval process.
- All Veterinary Natural Health Products are considered drugs under the Food and Drug Regulations and are subject to Division 8 requirements of the Regulations.
6.1.1 Veterinary Biologics
- The Canadian Food Inspection Agency (CFIA) is responsible for regulating and licensing
veterinary biologics and veterinary biologics manufacturing facilities in Canada, under the
Health of Animals (1990, c. 21) Act and the Health of Animals Regulations (C.R.C., c. 296). - Veterinary biologics: Guidance document and forms.
- Veterinary biologics licensed in Canada – list by species and by manufacturer.
6.1.2 Novel Animal Feeds
- CFIA also regulates novel livestock feeds under the Feeds Act (R.S., 1985, c. F-9) and the
Feeds Regulations, 1983 (SOR/83-593).
- Novel Feeds information at CFIA Novel feeds including frequently asked questions.
6.2 United States
As defined by section 201(v) of the Federal Food, Drug, and Cosmetic Act.
The term "new animal drug" means any drug intended for use for animals other than man, including any drug intended for use in animal feed but not including such animal feed.
As defined by section 201(w) of the Federal Food, Drug, and Cosmetic Act),
The term "animal feed" means an article which is intended for use for food for animals other than man and which is intended for use as a substantial source of nutrients in the diet of the animal, and is not limited to a mixture intended to be the sole ration of the animal.
“Veterinary biologics” are vaccines, bacterins, diagnostics, etc, which are used to prevent, treat, or diagnose animal diseases.
- The Center for Veterinary Medicine (CVM), within the FDA, regulates new drugs intended for animal use under the Federal Food, Drug, and Cosmetic Act and its amendments. The responsible office within CVM is the Office of New Animal Drug Evaluation (ONADE). - Animal drug regulations are codified in the Code of Federal Regulations (Title 21) Food and
Drugs. Regulations specific to new animal drug applications can be found in Part 514 (PDF / 36 pages) of the C.F.R. 21. Parts 500 to 599 in Subchapter E – Animal drugs, feeds and related products (PDF: 2 MB / 582 pages) may also apply.
- New Animal Drug Application: Guidance documents.
- Animal Drugs @ FDA – database of all animal drugs approved for safety and effectiveness. Page includes links to the eight sections of the “Green Book”. Records provide product details including dosage.
6.2.1 Veterinary Biologics
- The Animal and Plant Health Inspection Service (APHIS) regulates veterinary biologics (vaccines, bacterins, antisera, diagnostic kits, and other products of biological origin) under the Virus-Serum-Toxin Act (PDF: 17KB) and the Code of Federal Regulations (Title 9) Animals and Animal Products, Chapter 1, Parts 101 t0 123. Also available as Subchapter E – Viruses, serums, toxins, and analogous products; organisms and vectors (Parts 101-124). (PDF: 810KB / 195 pages, January 1, 2011).
- Veterinary biologics: Regulations and guidance documents.
6.2.2 Animal Feeds
- Animal feeds are regulated by the Division of Animal Feeds of the CVM, as covered by the
Federal Food Drug and Cosmetic Act (which defines food as "articles used for food or drink for man or other animals"). Therefore, supplements or additives to animal feeds “…are considered ‘foods,’ ‘food additives,’ or ‘new animal drugs’ depending on the intended use. - Mills that manufacture medicated feed must be licensed per the Animal Drug Availability
Act of 1996 and its regulations as codified in the Code of Federal Regulations (Title 21) Food and Drugs, Part 515 – Medicated feed mill license. (PDF: / 5 pages, April 1, 2011). - Guidance for Industry #120: Veterinary Feed Directive Regulation Questions and Answers
(PDF / 11 pages), March 26, 2009.
6.3 European Community
“Veterinary medicinal product” is defined in Directive 2001/82/EC12 as:
a) Any substance or combination of substances presented as having properties for treating or preventing disease in animals; or
b) any substance or combination of substances which may be used in or administered to animals with a view either to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.
The substance may be human, animal, vegetable or chemical.
- The European Medicines Agency (EMA) is responsible for the evaluation of human and veterinary medicines developed by pharmaceutical companies for use in the European Union. The scientific evaluations of veterinary medicines are carried out by the Committee for Medicinal Products for Veterinary Use (CVMP).
- EU legislation and procedures for the regulation of medicinal products for veterinary use – see Volumes 4 and 5-9 of The Rules Governing Medicinal Products in the European Union. - European Medicines Agency’s collection of information relating to veterinary medicines and
their regulation.
12
Directive 2001/82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to veterinary medicinal products
- European Public Assessment Reports (EPARs) for veterinary medicines that have been granted a Community marketing authorisation by the European Commission. Search options for this database include browse by species. Records provide extensive information.
