Language selection

Government of Canada / Gouvernement du Canada

Search

Clinical Trials For Natural Health Products

The Natural Health Products Directorate (NHPD) has changed its name to the Natural and Non-prescription Health Products Directorate (NNHPD) subsequent to its recently expanded mandate to include the oversight of non-prescription and disinfectant drugs in addition to natural health products (NHPs). Please note that we are currently modifying documents to reflect this change.

Thank you for your patience and understanding.

Health Canada has amended the Natural Health Products Regulations. Health Canada has also updated the evidence requirements for homeopathic medicines to align with products making similar claims. For more information and to access the supporting Labelling of Natural Health Products guidance document, visit What's new: Natural and non-prescription health products.

About This Guidance Document

This guidance document is designed to assist organizations and individuals in applying for authorization to conduct a clinical trial for a natural health product (NHP) in Canada. The legal requirements for clinical trials for NHPs in Canada are found in Part 4 of the Natural Health Products Regulations (NHPR). The Natural and Non-prescription Health Products Directorate (NNHPD) in the Health Products and Food Branch of Health Canada administers the NHPR.

Guidance documents do not have the force of law, but provide suggestions about how to meet the legal requirements. Alternate approaches that meet the legal requirements may be acceptable but should be discussed in advance with the NNHPD to avoid failure to comply with statutory or regulatory requirements. The NNHPD may ask for information, material or changes not indicated in this guidance document, but required as per the NHPR.

The NNHPD is the directorate of Health Canada responsible for authorizing or denying permission to conduct a clinical trial for a NHP. Information from clinical trials is used in assuring the safety, efficacy and quality of NHPs. The process of applying for authorization to conduct a clinical trial is designed to ensure the safety and ethical treatment of human experimental subjects and other persons involved in the trial. Adequate protocols and procedures for each clinical trial are required to provide a reasonable expectation that the trial objectives will be met.

Not all clinical trials of NHPs require authorization from Health Canada . This guidance document includes information on which types of clinical trials of NHPs do not require authorization.

This Clinical Trials for Natural Health Products Guidance Document should be read in parallel with the NHPR. The regulations were published in Canada Gazette, Part II, on June 18, 2003. An electronic version of the regulations is available on the internet. In this guidance document, references to relevant sections of the NHPR are enclosed in square brackets.

This guidance document refers to other NNHPD documents found on the internet. Documents of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) may be useful in preparing a Clinical Trial Application (CTA). These documents can be found on the ICH website.

Table of Contents

1.0 Clinical Trials for Natural Health Products

1.1 Regulatory Overview

According to section 1(1) of the NHPR, a NHP is:

"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 function in humans; or (c) modifying organic functions in humans."

However, an NHP does not include a substance set out in Schedule 2 of the NHPR, any combination of substances that includes a substance set out in Schedule 2 or a traditional medicine that is or includes a substance set out in Schedule 2.

An NHP also does not include a substance that is listed or within any limitations specified in Part I or Part II of Prescription drug list (prescription drugs) to the Food and Drug Regulations, or a combination of substances or traditional medicine that contains an ingredient that is listed or within any limitations specified in Part I or Part II of Prescription drug list [Section 2(2) of the NHPR] (Prescription drug list).

Consult the Evidence for Homeopathic Medicines Guidance Document for information on substances allowed in homeopathic medicines regulated by the NNHPD.

For an overview of the NHPR, please refer to Overview of the NHP Regulations Guidance Document. Part 4 of the NHPR describes what is required for clinical trials using an NHP. The requirements of a clinical trial (CT) with an NHP are similar to the requirements for a CT of a conventional pharmaceutical as described in Division 5 of the Food and Drug Regulations, but Part 4 of the NHPR takes into consideration the unique aspects of CTs for NHPs.

The scope of Part 4 of the NHPR is to ensure:

General requirements for CTs for NHPs are set out in Part 4 of the NHPR:

Parts of the NHPR Regulations that do not apply to NHP CTs:

1.2 When a CTA Should Be Submitted to the NNHPD

1.2.1 Inadequate evidence to support safety and efficacy of an NHP in humans

A CT may be needed:

Evidence requirements for combination products are described in section 12 of the Evidence for Safety and Efficacy of Finished NHPs Guidance Document.

Evidence requirements for traditional products are described in section 2.2.2 of the Evidence for Safety and Efficacy of Finished NHPs Guidance Document. A traditional product is (1) based on the theories, beliefs and experiences indigenous to different cultures, whether explicable or not, used in the maintenance of health, or in the prevention, diagnosis, improvement or treatment of a physical or mental illness and (2) a product for which the traditional use extends back at least fifty years. CTs may be required for traditional products that are not being used in a traditional manner, or any other NHP depending on the available evidence to support their safe and efficacious use.

Evidence requirements for homeopathic medicines are described in the Evidence for Homeopathic Medicines Guidance Document.

1.2.2 Comparative bioavailability

Comparative bioavailability studies evaluate the pharmacokinetics of two NHP formulations in healthy adult volunteers. This type of study is useful to determine the pharmacokinetic properties of an NHP and as a practical matter, is usually done with a single chemical entity. For example, a company has an NHP that is identical to another NHP currently on the market. A comparative test could be conducted for the two NHPs to determine if the new NHP has the same bioavailability as the existing NHP.

1.2.3 N-of-1 trials

An N-of-1 trial is a randomized multiple crossover trial in a single subject. Groups of individual subjects are included in the trial design. The subject undergoes pairs of treatment periods, one period with the active substance and one with the matched placebo. The key criteria for an N-of-1 trial are that:

For further information on N-of-1 trials, please refer to the following sources:

Guyatt G, Jaeschke R, McGinn T. Therapy and validity:N-of-1 randomized controlled trials. User's guides to the medical literature: A manual for evidence based clinical practice. Chicago, IL : American Medical Association, 2002: 275-290.

Guyatt G, Sackett D, Adachi J, Roberts R, Chong J, Rosenbloom D, et al. A clinician's guide for conducting randomized trials in individual patients. CMAJ 1988; 139: 497-503.

1.2.4 Clinical trials involving both an NHP and a conventional pharmaceutical

1.2.4.1 NHP to be used to treat side effects of a conventional pharmaceutical

The NNHPD will authorize and monitor these types of CTs as long as the pharmaceutical is being used within its approved conditions of use. The term "within its approved conditions of use" means that the product is being used as per the product label/monograph approved by Health Canada. For pharmaceuticals, a product label/monograph is considered to be approved by Health Canada if the product has a DIN.

1.2.4.2 NHP versus conventional pharmaceutical taken by individuals in different arms of the trial

The NNHPD will authorize and monitor CTs involving a trial comparing an NHP versus a conventional pharmaceutical, as long as the pharmaceutical arm of the trial is a phase IV trial (i.e., the pharmaceutical is being used within its approved conditions of use (see section 1.2.4.1)). A comparator treatment arm is not required for clinical trials testing an indication of use of an NHP for which there is an established pharmaceutical treatment, unless it is unethical to use a placebo.

1.2.4.3 NHP to be used to increase efficacy of a conventional pharmaceutical

The NNHPD will authorize and monitor these types of CTs as long as the pharmaceutical is being used according to its approved conditions of use. The Pharmaceutical Drugs Directorate (PDD) will be consulted if deemed necessary. For these types of clinical trials, the CTA should be submitted to the NNHPD only. If a consultation with the PDD is required, the NNHPD will make additional copies of the application and forward it to the PDD.

This type of CT may include a number of different arms. For example, a trial could investigate an NHP and a pharmaceutical versus a pharmaceutical, an NHP and pharmaceutical versus a placebo, or any combination of the above.

1.2.5 NHPs for conditions of use not appropriate for self care

The NNHPD will authorize and monitor these types of CTs. Other directorates will be consulted if deemed necessary. For these types of clinical trials, the CTA should be submitted to the NNHPD only. If a consultation with other directorates is required, the NNHPD will make additional copies of the application and forward it to the appropriate directorate.

The Safety Factors found in section 9 of the Evidence for Safety and Efficacy of Finished NHPs Guidance Document can be used to determine if the NHP is suitable for self care.

According to section 3 of the Food and Drugs Act, the approved marketed label of an NHP cannot claim that the product is a treatment, prevention or cure for any of the diseases, disorders or abnormal physical states referred to in Schedule A. However, an NHP can be used in a clinical trial to treat, prevent or cure any of the diseases, disorders or abnormal physical states referred to in Schedule A because the product will be used under the care of a physician or dentist as appropriate.

1.3 When a CTA Should Be Submitted to the Pharmaceutical Drugs Directorate and not the NNHPD

1.3.1 NHP/pharmaceutical combinations

When the pharmaceutical is being used outside the conditions of use approved by Health Canada or is not approved for sale in Canada, the CT will be authorized and monitored by the PDD regardless of whether the NHP is being used to treat the side effects or to enhance the efficacy of the conventional pharmaceutical.

"Outside the conditions of use approved by Health Canada" means that the pharmaceutical is NOT being used as per the product label/monograph approved by Health Canada. For pharmaceuticals, a product label/monograph is considered to be approved by Health Canada if the product has a DIN.

1.3.2 NHP that contains a medicinal ingredient that requires a prescription

The PDD will authorize and monitor CTAs for which an NHP contains an ingredient that is listed on Part I or Part II of Prescription drug list of the Food and Drug Regulations. For example, a CT testing a multivitamin product that provides more than 10,000 IU of Vitamin A per day would need to be submitted to the PDD.

1.4 When a CTA Does Not Need to Be Submitted to Health Canada

1.4.1 Observational studies

These types of studies do not require authorization from Health Canada, but do require approval from a REB. An observational study is one where the investigators do not manipulate the use of, or deliver, an intervention (e.g. do not assign patients to treatment and control groups) nor collect samples from patients that are outside of routine care, but only observe patients who are (and sometimes patients who, as a basis of comparison, are not) exposed to the intervention, and interpret the outcomes. For example, a patient may approach a physician wanting to take a specific NHP. The role of the physician is to provide advice to the patient on whether or not the NHP is safe for use. The physician may want to conduct further analysis on information or on samples already collected from the patient as part of the patient's routine care. As this is within the scope of the physician's practice, this is not considered a CT. If additional samples (i.e. samples that are not part of routine care) are collected via invasive or non invasive procedures (e.g. blood or urine) from the patients to study the outcomes of the NHP, then the study would be considered a CT and would require authorization from Health Canada and the REB.

1.4.2 Phase IV clinical trials

These types of studies do not require authorization from Health Canada but require REB approval (see section 1.1 of this document).

2.0 Pre-CTA Consultation Meeting

The NNHPD invites sponsors to request a pre-CTA consultation meeting, if the sponsor feels it is necessary. Such consultations may be particularly useful for new active substances or applications that will include complex issues that may be new to Health Canada. If the only issue is whether the investigational product is an NHP, the sponsor (or delegated person) may simply contact the NNHPD CT Unit - Submission Management Division by email. The email should include 1) a detailed description of the investigational product and 2) a summary of the protocol.

The pre-CTA consultation meeting provides an opportunity for the sponsor to present relevant data, discuss concerns and resolve issues regarding the product and protocol. It also gives the NNHPD an opportunity to provide guidance on the acceptability of the proposed trial(s). The NNHPD will not provide guidance on the commercial development of the NHP.

Sponsors may invite the qualified investigator(s) and other persons who will be involved in the proposed trial(s) to attend the meeting. The sponsor and other persons have the option of attending the meeting in person or via teleconference.

Requests for a pre-CTA consultation should be submitted by the sponsor in writing to the NNHPD at the address in section 13 of this document. Requests should include a cover letter proposing three dates and times suitable for a pre-CTA consultation meeting. A request for a pre-CTA consultation should be provided to the NNHPD at least 30 days prior to the meeting date. The NNHPD will acknowledge the request for consultation, indicate the numbers of copies of the information to be provided, and confirm a pre-CTA consultation meeting date. Two weeks prior to the meeting, the sponsor must provide an agenda and the Pre-CTA Consultation Package (see outline below) clearly labelled with "Pre-Clinical Trial Application Consultation" on the outside of the envelope. The Pre-CTA Consultation Package should be sent to the address given in section 13 of this document.

The Pre-CTA Consultation Package should contain:

  1. The purpose of the meeting, including the questions or issues to be discussed
  2. A brief description and summary of the product in question, such as:
    • a quantitative list of all the medicinal ingredients and a quantitative list of non-medicinal ingredients
    • dosage form, proposed dose, and purpose
    • general chemistry and manufacturing information, such as a summary of the manufacturing process, impurity profile, stability data and finished product specifications
    • an overview of the market history of the product, including the regulatory status of the product worldwide
    • a brief summary of pre-clinical and clinical data relating to the product
  3. Information on the placebo and comparator, if applicable
  4. The purpose of the CT
  5. A copy of the most recent version of the CT protocol
  6. Informed Consent Form (if available)

The sponsor must record pre-CTA consultation meeting minutes and provide a draft of the minutes to the NNHPD within two weeks post-meeting. The minutes will be circulated for approval. The NNHPD may issue a Record of Decision (ROD) based on the meeting minutes. Both the minutes and the ROD will subsequently be part of the CTA to be submitted to the NNHPD (see section 3 of this document).

3.0 Clinical Trial Application

3.1 Submission Format

CTAs should be submitted in the Common Technical Document (CTD) format and consists of all components outlined below and in Appendix 2. The CTD format is a standard format prescribed by ICH for the submission of information to regulatory authorities in the ICH regions. The entire CTA must be submitted in hard copy and items marked with an asterisk (*) must also be submitted in an electronic format approved by Health Canada (e.g. on CD or diskette in PC compatible Word, WordPerfect or editable PDF format).

Two hard and two electronic copies of the CTA should be provided.

3.2 Module 1: Administrative/Clinical Information

A cover letter that provides a brief introduction to the proposed CT, the NPN, DIN-HM, or DIN of the NHP if applicable, as well as any waivers or justification for the submitted data package should be submitted as part of Module 1. The following information must also be included in Module 1:

Although the NHPR state that REB approval must be submitted at the time of application, it is understood that REB approval may be withheld until NNHPD authorization is granted. When this occurs, the REB Attestation form (or similar document) must be submitted (by fax or mail) to the NNHPD prior to commencement of the CT. Given that the sequence of approval may vary, the applicant must ensure that both the NNHPD and the REB have approved the identical protocol.

Similarly, if the information required to complete the Clinical Trial Site Information Form and the Qualified Investigator Undertaking form is not available at the time of application, these forms must also be submitted (by fax or mail) to the NNHPD prior to commencement of the CT at that site.

Forms/templates in Appendices 3, 5, 7, and 8 can be found online. Please note that faxed or electronic signatures are acceptable.

1.3 Electronic Review Documents
See section 3.1 of this document.

3.2.1 Investigator's Brochure

The Investigator's Brochure is widely acknowledged as a document required to support a clinical trial. In the case where some of this information normally included in an Investigator's Brochure is not available, the sponsor is expected to provide a strong scientific rationale for not including the missing data. This may include a long history of use by humans, in which case, the normal pre-clinical information (e.g. pharmacological properties) may be waived. The Investigator's Brochure is a stand-alone document and is assessed accordingly. It should provide strong support for the use of the product in the proposed CT and should be presented in this context. It is understood that NHPs are not conventional pharmaceuticals and that much of the information required in a conventional pharmaceutical Investigator's Brochure may not apply to an NHP. The NNHPD may request additional information when necessary.

Information regarding the format of the Investigator's Brochure can be found in the ICH Guidance Document Good Clinical Practice: Consolidated Guideline ICH Topic E6, section 7. Sponsors should always provide the most recent copy of the Investigator's Brochure with their CTA.

As identified in Guidance for Industry: Good Clinical Practice: Consolidated Guideline ICH Topic E6, components of an Investigator's Brochure are:

  1. Title page and table of contents
  2. Confidentiality statement
    This statement instructs the investigator to treat the Investigator's Brochure as a confidential document for the sole information of and use by the investigator's team, the REB and Health Canada.
  3. Summary of the product to be evaluated
    This section should include a brief summary highlighting the available significant physical, chemical, pharmacological, toxicological, and clinical information relevant to the stage of clinical development of the investigational product.
  4. Introduction
    This section should include a brief introductory statement that outlines the chemical name of the investigational product, all medicinal ingredients, the placebo and the comparator, and the rationale for performing research with the investigational product.
  5. Physical, chemical and, if any, pharmaceutical properties and formulation information
    This section is a summary of the information provided in the Quality Overall Summary (QOS)-NHP (CTA-Phases I/II/III) Template and should include a description of the investigational product including the chemical and/or structural formula, if known, the relevant physical, chemical and pharmaceutical properties; chemistry and manufacturing information; dosing information; and instructions for the storage and handling of the dosage form.
  6. Comprehensive summary of pre-clinical data
    This section should include the results of all available relevant pre-clinical pharmacological and toxicological studies. This summary should address the methodology used and the results and should discuss the relevance of the findings as well as any possible unfavourable and unintended effects in humans. The following sections should discuss the most important findings from the studies, including the dose response of observed effects, the relevance to humans and any aspects to be studied in humans.
    • pre-clinical pharmacology (e.g., pharmacokinetics in animals), if any
    • toxicology, which may include information from single-dose, repeated-dose, carcinogenicity, reproductive toxicity and genotoxicity (mutagenicity) studies
  7. Comprehensive summary of clinical data
    This section should include the following information, if any, on the effects of the investigational product in humans:
    • extrapolations from pre-clinical studies
    • clinical pharmacodynamics (e.g., dose-response relationship and mechanism of action)
    • clinical pharmacokinetics (e.g., absorption, distribution, metabolism and excretion)
    • history of use in humans, including the results of previously authorized completed trials (include in all subsequent CTAs)
    • discussion and evaluation of clinical results (i.e., effectiveness/efficacy and safety)
    • conclusions from clinical studies including:
      • benefit assessment and risk acceptability
      • effective and recommended clinical dose
      • interactions with other NHPs, foods or pharmaceuticals
      • cautions, warnings, contraindications and adverse reactions
      • rescue medication
      • any additional information (e.g., scientific monographs, expert opinion reports). The criteria for expert opinion reports are described in section 3.5 of the Evidence for Safety and Efficacy of Finished NHPs Guidance Document
  8. Marketing experience
    This section should identify countries where the NHP under investigation has been marketed or has obtained regulatory approval. The Investigator's Brochure should also identify all the countries where the investigational product was the subject of a licence application but did not receive approval/ registration for marketing or was withdrawn from marketing/registration. Product monographs, product information sheets or marketed/approved labels should be included in this section, if available.
  9. Summary of data and guidance for the investigator
    This section should provide an overall discussion of the clinical and non-clinical data and when possible, should summarize the information from various sources on different aspects of the investigational product.

The most recent version of the Investigator's Brochure must be submitted to the NNHPD at the time of application. Please include, in the title page of the Investigator's Brochure, the date the document was finalized.

For ongoing clinical trials, a revised Investigator's Brochure, with additional information and any changes highlighted should be submitted to the NNHPD annually. Please include, in the title page of the Investigator's Brochure, the date the document was revised. If an Investigator's Brochure is updated more frequently, it should be submitted as required.

For products being used outside the conditions of use approved by Health Canada, a copy of the currently approved product monograph, with the supplemental information supporting the conditions of use for the proposed trial, may be submitted in lieu of the Investigator's Brochure. For products not approved by Health Canada, the Investigator's Brochure must be submitted.

3.2.2 PCERT

The Protocol Synopsis and Evaluation Review Template (PCERT) originates from the Preclinical and Clinical Evaluation Review Template, which is no longer in use. The PCERT used by the NNHPD is similar to the PCERT used by the PDD. The PCERT serves to summarize the pertinent information described in the protocol (see section 3.2.3) and is used by the NNHPD as a review template to expedite the review process. Both a PCERT and a protocol are to be submitted in the CTA, but the NNHPD approves the information in the protocol, as it is the protocol that is distributed to the investigators conducting the CT. Furthermore, as per ICH guidelines Good Clinical Practice: Consolidated Guideline ICH Topic E6, section 6, ALL the information contained in the PCERT must be included in the protocol. Please ensure the information in the PCERT is consistent with the information in the protocol. All sections of the PCERT must be completed. For sections that are not relevant, please state "not applicable." Please do not erase any of the section headings when completing the PCERT.

3.2.3 Protocol

This document is distributed to all investigators involved in the clinical trial once the CT has been authorized by Health Canada and the REB. Guidelines for generating a CT protocol are located in the ICH Guidance Document Good Clinical Practice: Consolidated Guideline ICH Topic E6 section 6. While the protocol and PCERT will contain some of the same information, the protocol will describe the CT procedures in greater detail, and will also include a section on: direct access to source data/documents, ethics, and data handling and record keeping.

Some required items frequently omitted from the CT protocol exclusion criteria that should be included are:

3.2.4 Informed Consent Form

Guidelines for generating an Informed Consent Form are located in Appendix 6 and in the ICH Guidance Document Good Clinical Practice: Consolidated Guideline ICH Topic E6, section 4. Some required items frequently omitted from Informed Consent Forms that should be included are:

The language of the Informed Consent Form must be clear to the patients (e.g., "damage to the heart" instead of "cardiotoxicity").

3.3 Module 2: Common Technical Document Summaries

This module should include:

2.1 Common Technical Document Table of Contents

2.2 (Not applicable to clinical trials).

2.3 Quality Overall Summary

This section is intended to provide the applicant with guidelines to aid in completing the Quality Overall Summary-Natural Health Product Template (QOS-NHP Template) found in Appendix 7. This template is prepared in order to fulfill the quality (i.e. Chemistry and Manufacturing) requirements of the investigational product used in the clinical trial. This template should be used by the sponsor to summarize the information about the quality of medicinal substances and finished products that meet the definition of an NHP (see section 1.1 of this document) to be used in the CT. This quality overall summary is not required if the NHP to be used in the CT has been previously approved by Health Canada for a CT or for marketing, but appropriate cross-reference must be provided. With regard to previously approved CTA information, please provide confirmation that the information has not changed.

The purpose of these guidelines is to help the CTA submission sponsor understand the quality requirements referred in the QOS-NHP template. These guidelines should be followed when completing the QOS-NHP Template. Alternate approaches are acceptable provided they are supported by adequate scientific justification. Sponsors are advised to discuss in advance with NNHPD about alternate approaches in the completion of the quality requirements in their CTA submission to avoid rejection or withdrawal of the submission. Sponsors are encouraged to devote the sufficient time necessary to prepare a clear, precise QOS-NHP Template. The submission of an inaccurate or an incomplete template will result in greater expenditure of an Assessment Officer's time in reviewing and summarizing data which may delay the process.

In this template, section S refers to Substance (e.g., medicinal ingredients or raw material), while section P refers to Finished Product.

It is the sponsor's responsibility to complete those sections and fields that apply. It is understood that certain sections and fields may not be applicable and should be indicated as such by reporting "not applicable" in the appropriate area with an accompanying explanatory note describing the reasons for the inapplicability. The use of tabular format is encouraged to summarize information (e.g. in the specification for a medicinal substance when more than one substance is being used). The tabular format included in this template may need to be expanded, as necessary. These tables are included as illustrative examples of how to summarize information. Other approaches to summarize the information can be used if they fulfil the same purpose. If scanned images are incorporated into the document (e.g., extraction and isolation schemes, synthetic schemes, molecular structures), sponsors should ensure that resolution is sufficient for legibility.

Based on the NHP substances set out in Schedule 1 of the NHPR, medicinal ingredients have been divided into three categories under Part A. Select a category (from Part A) that applies to your product. If more than one category applies (e.g., in a combination product), complete the necessary combination of categories. To prepare the chemistry and manufacturing information for the finished product, complete Part B. The template in Part C for the Finished NHP Specifications is also required.

Sponsors are also encouraged to consult the Evidence for Quality of Finished Natural Health Products guidance document also available on our website when completing the QOS-NHP Template for further guidance on areas such as acceptable test methods and tolerance limits.

Introduction

The introduction section is intended to provide a brief summary of the investigational product, a brief summary of the clinical trial protocol, information about the comparator product if applicable, and a summary on previously submitted/approved information, e.g. DIN/NPN, if applicable.

The introduction should include proprietary name, non-proprietary name or common name of the investigational product, company name, dosage form(s), strength(s), route of administration, and proposed indication(s).

Sponsors may provide a contact person's name, phone number, fax number, and e-mail address for ease of communication.

Part A: Chemistry & Manufacturing Information of Medicinal Ingredient(s)

The following are the categories of substances from Schedule 1 of the NHPR for which specific quality requirements are described in detail below.

Category I: Plant, Plant material, Alga, Fungus, Bacterium, Non-Human Animal Material

Category II: Isolate, Synthetic Duplicate, Non-Standardized and Standardized Extract, Amino Acid, Essential Fatty Acid, Vitamin, Minerals

Category III: Probiotics

2.3.S Medicinal Ingredient(s)

This section is intended to provide the quality requirements of the medicinal ingredients to be used in the finished product. Considering the variety of NHPs used as medicinal substances (as indicated in Schedule 1 of the NHPR), this section highlights the chemistry and manufacturing requirements of the medicinal ingredients to review their quality, stability and safety. If some of the information included under this section is not available to the sponsor from the supplier or is proprietary in nature, the NNHPD has a mechanism called the Natural Health Product Master File (NHPMF), where the supplier can supply any proprietary information concerning their products directly to the NNHPD in the form of a NHPMF. The supplier would then be considered the NHPMF Holder. This NHPMF will be held in strict confidence and will be used in support of the CT submission only upon receipt of written authorization from the supplier/NHPMF Holder of the medicinal ingredient (i.e., via a letter of access issued to the NNHPD).

The sponsor should be able to provide most of the information on the medicinal ingredient, except possibly the proprietary information found in section 2.3.S 2.2 of QOS-NHP template. It is the responsibility of the sponsor to obtain all other information from the supplier of the medicinal ingredient and include this in the clinical trial submission package.

Regardless of the information provided by the supplier of the medicinal ingredient, the manufacturer of the final dosage form is responsible for ensuring that acceptable specifications and analytical procedures are in place for the finished product.

2.3.S.1 General Information

In the general information section, the sponsor needs to provide the information for the medicinal ingredient. For the identity of organisms (plants, algae, fungi, bacteria, and non-human animals), the applicant should provide the common name of the organism, its proper name consisting of the Latin binomial of genus and specific epithet, and strain number in the case of probiotics, and a description of the part used where applicable (e.g. leaf). For chemicals (isolates, amino acids, fatty acids, their synthetic duplicates and derivatives), the information required in this section includes an unambiguous name, structural information such as the structural and molecular formula; a physical description, for example organoleptic properties; and the source material (derivative, source organism, or synthesis), and any other relevant information that can help in identifying a specific characteristic of the medicinal ingredient.

In addition to physical methods of identification of plant materials, chemical fingerprint testing, e.g., TLC, HPLC or HP-TLC analysis, must be performed to properly characterize the identity of the plant since there are often similar-looking varieties of the same species with different chemical and pharmacological properties.

2.3.S.2 Manufacturing Information

2.3.S.2.1 Manufacturer(s)

The manufacture section is intended to provide the contact information and responsibilities of each manufacturer and contractor including each proposed production site and facility involved in manufacturing the batches. This includes the facilities involved in the fabrication, packaging, testing, importing, storage and distribution of the medicinal ingredient used in the clinical studies.

2.3.S.2.2 Description of Manufacturing process and Process Controls

A flow chart and brief description of the manufacturing process and process control should be provided that describe the extraction, synthesis or isolation of the medicinal ingredient, and process conditions such as temperature, pH, drying, aeration, or specific fermentation conditions. As an example, a flow diagram of the synthetic process(es) should include chemical structures of starting materials, intermediates, reagents and drug substance while a flow diagram of an isolation procedure should includes source material, solvents used for extraction, conditions of extraction and purification procedure. See the example of a flow diagram given below.

Flow Diagram Showing Manufacturing Process and Process Conditions

Flow Diagram Showing Manufacturing Process and Process Conditions

This flow chart is an example to highlight the manufacturing process.
Provide product specific steps and process conditions where it is marked as ?

Medicinal ingredients that are of animal origin or have been processed using animal material should be free of the causative agents of Bovine Spongiform Encephalopathy (BSE)/Transmissible Spongiform Encephalopathy (TSE). A completed Animal Tissue Form (found in Appendix 3 of the Clinical Trials for Natural Health Products guidance document) should be provided.

If a NHPMF or a Drug Master File (DMF) is filed with Health Canada and cross-referenced for certain proprietary information (e.g., section 2.3.S 2.2 of QOS-NHP template), provide the NHPMF number or the DMF number assigned by Health Canada and a copy of the letter of access from the manufacturer allowing the NHPMF to be used in support of the clinical trial submission. It should be ensured that the information included in the NHPMF or DMF is up to date (e.g., updated every two years) and that the data has been received by Health Canada. If a Canadian agent is used by the NHPMF or DMF holder, a letter from the NHPMF or DMF holder should be submitted allowing the agent to act on their behalf, rather than the letter coming from the Canadian agent.

2.3.S.3 Characterization

2.3.S.3.1 Identification of Medicinal Ingredient

This section should include a list of studies performed and conclusions from the studies to confirm the structure of the medicinal ingredient. The studies carried out to elucidate and/or confirm the identity of organisms such as plants as medicinal ingredients includes physical descriptions and chromatographic/DNA fingerprinting studies. For the identification of the chemical structure of the new medicinal ingredient the following types of evidence are normally included: elemental analysis, GC, HPLC, LC-MS, IR, UV, MS, and/or NMR. This list is by no means exhaustive, but provides an indication as to the types of information that could be included.

For well known medicinal substances, it is sufficient to provide copies of the studies performed on the NHP from the proposed suppliers run with a suitable reference standard.

A discussion should be included of the possible isomers that can result from the manufacturing process, the steps where they were introduced, and a summary of the results of the studies carried out to investigate the physical, chemical, and biological properties of these isomers. If there is a preferred isomer or isomeric mixture, the medicinal substance specification should include a test to ensure isomeric identity and purity. If the medicinal substance is a single isomer or a fixed ratio of isomers, provide the rationale for this decision.

Foreign matter tests are important to ensure that the plant, fungal, algal, or non-human animal material is entirely free from visible signs of contamination such as sand, dirt, insect parts, glass and metal. Testing should be done according to WHO or Pharmacopoeial methods.

Determination of acid-insoluble ash is important to measure the amount of inorganic impurities in the form of extraneous (non-physiological) materials in a plant, fungal, algal, or non-human animal material. Testing should be done according to USP, Eur.Pharm, or WHO methods.

Loss on drying is required where a substance is known to be hygroscopic. The loss on drying procedure (such as drying in an oven) may be adequate, but in some cases (e.g. volatile (essential) oil containing plants), a detection procedure that is specific for water content is required (e.g. Karl Fischer method).

2.3.S.3.2 Impurities

The tables in the QOS-NHP template can be used to summarize the names, structures, test methods, and limits of detection of the impurities. The sponsor is responsible to provide the identity of any product and process related impurities and their limits. It should be ensured that actual numerical results are provided rather than vague statements such as "within limits" or "conforms". If more than one batch is used, complete a table for each batch.

For plant materials the nature of the chemical fertilizers and pesticides used should be recorded, if these have been employed during cultivation.

2.3.S.4 Control of the Medicinal Ingredient

This section is intended to summarize the specifications for the medicinal ingredients to be used in finished product. The specifications are a list of tests, references to analytical procedures, and appropriate tolerance limits, which are numerical limits, ranges, or other criteria for the tests described. This would include tests for description, identification, purity, quantity and potency as well as other tests specific to the medicinal ingredients. The specifications can be summarized according to the table in the QOS-NHP template including the Tests, Test Methods, and Tolerance Limits. The Test Method should indicate the kind of analytical procedure used (e.g., visual, IR, UV, HPLC, Atomic Absorption, Mass Spectrometry etc.) and a brief description of any in-house method. It should be ensured that actual numerical results are provided for the Tolerance Limits, rather than vague statements such as "within limits" or "conforms".

Please refer to the Evidence for Quality of Finished Natural Health Products guidance document for further information

If different batches of the ingredients are being used, a description of the batches and results of batch analyses should be provided. Analytical results should be either summarized in the QOS-NHP template or provided as a copy of the Certificate of Analysis for each batch used in the clinical trial. Batch number, batch sizes and dates and sites of production should also be provided.

2.3.S.6 Container Closure System

Information about any specific storage conditions required for maintaining the quality of the medicinal ingredients or for its shipment should be provided along with a description of the container closure system(s).

2.3.S.7 Stability

In this section actual stability results (i.e., raw data) used to support the clinical trial should be provided. Full long term stability data may not be required at the time of filing, provided some preliminary stability data is available (e.g. accelerated stability data) on representative batches together with a commitment that the stability of the clinical trial samples will be monitored throughout the duration of the trial. It should be ensured that actual numerical results are provided rather than vague statements such as "within limits" or "conforms".

Part B: Chemistry & Manufacturing Information of the Finished Product

2.3.P FINISHED NATURAL HEALTH PRODUCT

2.3.P.1 Description and Composition of the Finished Product

A description of the finished product and its composition should be provided. The description of the finished product dosage form should include the physical description, proposed strength(s), release mechanism (dissolution and/or disintegration) and any other distinguishable characteristics (e.g., "The proposed finished product is available as oval, brown capsule with disintegration time of 45 min. in two strengths: 100 mg and 250 mg").

Composition should express the quantity of each medicinal and non-medicinal ingredient on a per dosage basis (e.g., mg per capsule) and percentage basis including a statement of total weight of the dosage unit.

Each ingredient should be listed by its proper or common name, quality standards (e.g., USP, Ph.Eur., House, etc.) and, if applicable, their grades (e.g., USP NF). The quantitative composition should be provided for all proprietary mixtures or blends of medicinal ingredients. The identity and quantity of all dyes and marking inks must be provided (e.g. Cochineal Red, FD&C Blue No. 1).

If applicable, a quantitative list of all components of the placebo sample used in the clinical trial should be provided.

2.3.P.2 Formulation Development

The sponsor needs to provide any available discussion on the development of the dosage form, the formulation, manufacturing process for a new combination, standardized extract, or complex dosage form such as a transdermal patch.

2.3.P.3 Manufacturing Information of the Finished NHP

2.3.P.3.1 Manufacturer(s)

Similar to section 2.3.S.2.1, this section should include the contact information of the facility involved in fabrication, packaging, testing and storage.

If a NHPMF or a DMF is filed with Health Canada and cross-referenced for certain proprietary information (e.g., section 2.3.P. 3.1 of QOS-NHP template), provide the NHPMF number or the DMF number assigned by Health Canada and a copy of the letter of access from the manufacturer allowing the NHPMF to be used in support of the clinical trial submission. It should be ensured that the information included in the NHPMF or DMF is up to date (e.g., updated every two years) and that the data has been received by Health Canada. If a Canadian agent is used by the NHPMF or DMF Holder, a letter from the NHPMF or DMF holder should be submitted allowing the agent to act on their behalf, rather than the letter coming from the Canadian agent.

2.3.P.3.2 Batch Formula

A batch formula should be provided that includes strength, batch size, date and a list of all components on a per batch basis including a statement of the total weight or measure of the batch. This should include all components used in the manufacturing process, regardless if they appear in the finished product. All overages for individual ingredients should be clearly indicated that could have been used to compensate any possible manufacturing losses. If more than one batch is produced (e.g., additional lots of finished product or different strengths), complete the batch formula analysis for each batch.

2.3.P.3.3 Description of Manufacturing process and Process Controls

A flow diagram should be provided giving the steps of the manufacturing process and process control. This information should include the process parameters (e.g., temperature, mixing time, mesh size, etc.) that are specific to finished product manufacturing. For sterile products, details and conditions of sterilization and/or lyophilization should be provided. See the example of a flow diagram given in section 2.3.S.2.2.

2.3.P.4 Control of Non-medicinal Ingredients

Confirmation should be provided if a non-medicinal ingredient (NMI) used is included in the NNHPD's List of Acceptable Non-medicinal Ingredients. For NMIs obtained from non-human animal origin, an Animal Tissue Form should be submitted that includes the name of the material, its source and country of origin of that source material. Specified Risk Materials for the transmission of BSE/TSE must not be used.

Confirmation should be provided that none of the NMIs which appear in the finished product are prohibited for use in drugs by the Canadian Food and Drug Regulations.

For NMI(s) used for the first time in a finished NHP or by a new route of administration (novel NMIs), full details of the manufacturing, characterization, and controls, with cross references to supporting safety data (non-clinical and/or clinical) should be provided.

2.3.P.5 Control of Finished NHP

2.3.P.5.1 Specification(s)

The Control of the Finished Product section is intended to summarize the specifications for the finished product. The specifications are a list of tests, references to analytical procedures, and appropriate tolerance limits which are numerical limits, ranges, or other criteria for the tests described. This would include tests for identity, purity, quantity and potency as well as other tests specific to the finished NHP. The specifications can be summarized according to the table in the QOS-NHP template including Tests, Test Methods, and Tolerance Limits. The Test Method should indicate the kind of analytical procedure used (e.g., visual, IR, UV, HPLC, Atomic Absorption, Mass Spectrometry, etc.). It should be ensured that actual numerical results are provided for the Tolerance limits, rather than vague statements such as "within limits" or "conforms".

Particle size may have a significant effect on disintegration rates, product use characteristics (e.g. if too fine powder will escape tea bag), bioavailability, and/or stability, particularly for plant or fungal materials intended for use in herbal teas or solid medicinal products. Particle size determination may also be required for preparations of isolates, vitamins, etc., depending on the finished product, e.g. time-released capsule. Testing may be done according to Pharmacopoeial methods depending on the finished product characteristics.

Please refer to the Evidence for Quality of Finished Natural Health Products guidance document for further information on the specifications of the finished product.

2.3.P.5.4 Batch Analyses

If there is more than one batch of the finished product used in the clinical trial, a description of the additional batches accompanied with a batch analysis should be provided. The batch number, batch sizes and dates and sites of production should be stated in the table. If available, a Certificate of Analysis should be provided for each batch.

2.3.P.5.5 Characterization of Impurities

Information on the characterization of any product and process related impurities and their limits impurities should be provided. This information should include degradation products, possible microbial and chemical contaminants, and solvents used in the manufacturing process of the finished product. A copy of the tables in the QOS-NHP template in section 2.3.S.3.2 can be used to summarize this information.

2.3.P.7 Container Closure System

Information about any specific storage conditions required for maintaining the quality of the finished product should be provided along with a description of the container closure system(s).

2.3.P.8 Stability

The types of studies conducted to support the stability of the finished product, protocol used, and the results of the studies should be summarized in the stability section. The tables in the QOS-NHP template can be used to summarize the stability information required of the batches used in the clinical trial. Full long term stability data may not be required at the time of submission, provided accelerated stability testing is performed with a commitment that the stability of the clinical trial samples will be monitored throughout the duration of the trial. The actual stability results (i.e., raw data) used to support the clinical trial should be provided. It should be ensured that actual numerical results are provided rather than vague statements such as "within limits" or "conforms.

Part C: Finished Natural Health Product Specifications Template

This template should be completed and signed, and for any revisions in the finished product specifications, a revised copy of this template should be submitted.

3.4 Module 3: Quality Data

This module should include any supporting data that is not being captured in the QOS- NHP Template, such as signed and dated specifications, certificates of analyses, Animal Tissue Form (Appendix 3f), expert reports, published papers and signed attestation. The following sections are included in Module 3:

Clearly label the envelope containing the CTA with "Attention: Clinical Trial Unit" and send to the address in section 13 of this document.

4.0 Review Process

Note: A phase I-III clinical trial cannot begin until authorization from Health Canada and the REB has been received by the sponsor.

4.1 Level 1: Verification

The NNHPD screens CTAs and gives the CTA a company file number and submission number. The NNHPD then sends out an acknowledgement notice confirming the receipt of the CTA. The letter lists the file and submission number and notes the date of receipt. Applicants should use the file number assigned on all subsequent correspondence about the CTA.

4.2 Level 2: Processing

The NNHPD verifies that all information is correctly identified in all application forms (Appendix 3) submitted and that all appropriate supporting information is submitted and in acceptable format (see section 3 of this document). Faxed or electronic signatures are accepted in lieu of original signatures.

When minor deficiencies are identified, clarification will be obtained through e-mail or a telephone call. For major deficiencies, the NNHPD will issue a Processing Deficiency Notice (PDN) requesting the missing information or clarification related to the completeness of the CTA forms and supporting information. The PDN is faxed directly to the Contact for this Application (identified in the Clinical Trial Application and Attestation Form), who may be the sponsor, the sponsor's representative in Canada or a consultant. The recipient is allowed up to 30 days to provide an adequate response. An adequate response is considered to be the provision of the requested data, or a strong scientific justification why this data is not required. Once all of the concerns have been addressed, the CTA will proceed to level 3.

4.3 Level 3: Assessment

When the application reaches this level, the clinical and quality data packages will be reviewed to determine if the CT is suitable for authorization. If more information is required to make a judgment, concerns will be outlined in an Information Request Notice (IRN). The sponsor will be given up to 30 days to respond. If the response to the IRN is incomplete or the NNHPD identifies new concerns based on the responses provided by the applicant, the NNHPD will issue another IRN. When all concerns are adequately addressed by the applicant, the CTA will proceed to level 4.

In responding to an IRN, the sponsor should follow these procedures:

4.4 Level 4: Decision

If the decision is to approve the CT, a Notice of Authorization, addressed to the sponsor, will be faxed to the Contact for this Application (identified in the Clinical Trial Application and Attestation Form).

Health Canada will not grant authorization if there are reasonable grounds to believe, based on assessment of the application, that:

Once a Notice of Authorization is issued by the NNHPD, the sponsor may start the trial at any time, but must notify the NNHPD 15 days prior to the commencement of the trial (see section 13 of this document). The sponsor should also inform the NNHPD when the trial has been completed. At this time, the Notice of Authorization does not have an expiry date.

5.0 Notifications

Changes can be made to an approved CTA or CTA-Amendment (CTA-A) but must be submitted to the NNHPD in the form of either a notification (see below) or an amendment (see section 6 of this document). The type of change determines whether a notification or an amendment is required. In either case, if NNHPD approval is obtained before REB approval, all changes to the CTA requested by the REB must be communicated to the NNHPD through a notification or an amendment.

If a change to the protocol of an approved CTA increases the safety or quality of the trial, and if no aspects of the risks to people are increased, then a notification to the NNHPD is appropriate. The changes may be implemented immediately, but the NNHPD must be informed in writing within 15 calendar days [Section 70 of the NHPR].

Types of changes requiring notification:

Changes to the protocol that increase or do not affect the safety of the trial and would not be considered an amendment, under section 6 of this document. For example:

Changes to the quality (chemistry and manufacturing) information that do not adversely affect the quality or safety of the NHP, for example:

A notification submitted to the NNHPD should include a cover letter outlining the changes made to the CTA and any supporting documentation (e.g., any of the forms in Appendix 3). The information will be reviewed and added to the file. Notifications may be sent by FAX (613) 954-2877 or mail (see section 13 of this document).

The NNHPD will notify the applicant if the changes made to the CTA need to be re-submitted to the NNHPD as an amendment.

6.0 CTA Amendment (CTA-A) or New CTA

6.1 When Changes to an Approved Clinical Trial Require an Amendment

Some changes to an approved CTA require that a CTA-A be submitted to the NNHPD. Changes to an approved CT can only be implemented once authorized by both the NNHPD and the REB unless the subject's health is at risk (see section 6.1.1 of this document). In other cases, changes to a CT are so substantive that a new CTA will be needed (see section 6.2 of this document).

Sponsors must file a CTA-A [Section 71 of the NHPR] when changes to the protocol:

Changes to the protocol that require a CTA-A include:

Changes to quality (chemistry and manufacturing) that require a CTA-A include:

Changes to the chemistry and manufacturing may require revisions to Module 1 as well as Modules 2 and 3.

6.1.1 Implementing changes described in amendments

Amendments can be implemented immediately if the safety of the subjects or other persons is at stake [Section 71(2) of the NHPR]. Amendments which increase the risk to subjects or other persons must not be implemented until authorized. The NNHPD will issue a Notice of Amendment to the sponsor once it has been approved by the NNHPD. If changes were not implemented earlier due to safety reasons, the newly amended protocol can be implemented upon receipt of the Notice of Amendment and REB approval.

6.1.2 CTA-A contents

The contents of a CTA-A are described in section 71(3) of the NHPR. They include:

Send the contents of the CTA-A to the NNHPD at the address in section 13 of this document. Clearly label the outside of the envelope with "Attention Clinical Trial Unit"

6.2 When Changes to an Approved Clinical Trial Require a New CTA

Note that certain fundamental changes to an NHP of an approved CTA should be submitted as a new CTA, with reference to the previously approved CTA. These changes include:

Changes to safety and efficacy that require a new CTA include:

Changes to the quality information that require a new CTA include:

7.0 Continuous Assessment

7.1 Refusals by Research Ethics Board or Other Regulatory Authority

Following Health Canada approval of a CTA or CTA-A, information regarding refusals by a REB or other regulatory authority should be submitted as a notification.

7.2 Adverse Reactions

Definitions of an adverse event, adverse reaction, serious adverse reaction and serious unexpected adverse reaction can be found in the Glossary of this document.

Sponsors of CTs must maintain records of all adverse events associated with the NHP that have occurred inside or outside Canada [Section 76(3)(c) of the NHPR]. These records shall include information on dosage form, and the use and purpose of the NHP at the time of the adverse event. These records must be maintained for 15 years. If there are reasonable grounds for concern, including if the trial involves a risk to health of a CT subject or other person, records must be made available to the NNHPD no later than two days after the day the request is received. In any other case, records must be provided within seven days of a request [Section 77 of the NHPR].

7.2.1 Expedited reporting

During the CT, the sponsor is required to inform the NNHPD Clinical Trial Unit of any serious unexpected adverse reaction to the NHP that has occurred inside or outside Canada [Section 78 of the NHPR, ICH Guidance Document E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting].

Serious adverse events unrelated to the NHP being studied do not require expedited reporting to the NNHPD. In situations in which the cause of the adverse event is uncertain, the report should be submitted in the expedited manner and the problem in ascribing a cause should be addressed in a cover letter. For further information, please refer to ICH Guidance Document E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.

Each serious unexpected adverse reaction to an NHP should be reported individually in accordance with the data elements specified in the ICH Guidance Document E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. Expedited adverse reaction reports for CTs should be submitted by fax to the Clinical Trial Unit, NNHPD (FAX (613) 954-2877).

7.3 Other reports requiring accelerated reporting

Other situations than those described above may require rapid communication to the NNHPD. Appropriate scientific and medical judgment should be applied to each situation.

For example, the discovery of information that might influence the risk-benefit assessment of an NHP, or that would be sufficient to consider changes in dose administered or in overall conduct of a CT, should be communicated rapidly. Specific examples include:

For further information refer to the ICH Guidance Documents: E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting and E6: Guideline for Good Clinical Practice.

All adverse reaction reports should be submitted by fax to the Clinical Trial Unit using the form found in Appendix 8 or a similar form containing the same information. Please fax this form to (613) 954-2877.

8.0 Discontinuation of a Clinical Trial

If the sponsor prematurely discontinues an NNHPD authorized trial, in its entirety or at a CT site inside or outside of Canada, the NNHPD must be notified within 15 calendar days after the date of discontinuance [Section 79 of the NHPR]. The notification should include:

The sponsor may resume the trial in its entirety (through a CTA-A) or at a site that was previously discontinued (notification) if the sponsor submits the following information [Section 79(2) of the NHPR]:

9.0 Suspension and Cancellation

Health Canada can suspend authorization of the use of an NHP in a CT or at a particular CT site if it appears that:

Normally before suspending a CT, the NNHPD will send the sponsor a notice stating that the authorization may be suspended in its entirety or at a specific CT site and the reason for the suspension. Suspension will begin 30 days after the day on which the notice is received, unless the sponsor provides, within the 30 days, information demonstrating that the authorization should not be suspended because the situation giving rise to the suspension did not exist or has been corrected [Section 80(2) of the NHPR].

If there are reasonable grounds to believe suspension is needed to prevent harm to the participants of the CT or another person, the NNHPD will suspend the CT in its entirety or at a particular CT site before giving the sponsor an opportunity to respond [Section 81 of the NHPR]. In this case, the NNHPD will send the sponsor a notice giving the reason for the suspension, the day the suspension begins and indicating if the authorization is suspended in its entirety or at a particular CT site.

The authorization for the CT will be restored if, within 30 days after the day on which the suspension is effective, the sponsor provides the NNHPD with information demonstrating that the situation causing the suspension either did not exist or has been corrected. If the required information has not been received by the NNHPD within 30 days after the day on which the suspension is effective, the authorization for the CT will be cancelled in its entirety or at a particular CT site [Section 82 of the NHPR].

10.0 Labelling and Instructions For Use of an NHP

The label of the NHP to be used in a CT must conform to the requirements in section 75 of the NHPR.

The sponsor must ensure that the label of the NHP provided to the investigators has the following information in both official languages:

Written instructions on how to use the study product(s) should be provided to the subject as part of the Informed Consent Form.

11.0 Records

The sponsor must keep records of the CT [Section 76 of the NHPR]. The records must be created and stored in a way that allows complete and accurate reporting of the trial. Records should be adequate to indicate that the CT has been conducted in accordance with GCPs and the NHPR, and must include a copy of the Notice of Authorization from Health Canada.

Records should include:

The sponsor must maintain printed copies of all of these records for a period of 15 years.

Records must be made available to the NNHPD within two days if there is a concern that the use of the NHP for the purposes of the CT may endanger the health of the subjects involved in that trial, that the CT is contrary to the best interests of the subjects, that GCPs are not being followed, or that information about the trial submitted to Health Canada was false or misleading. In any other case, records must be provided within seven days of a request [Section 77 of the NHPR].

12.0 Roles and Responsibilities of Those Involved in Clinical Trials

Note that one person may have one or more roles in the clinical trial. Some of the terms defined in this section appear in the application form(s) in Appendix 3.

Sponsor - A sponsor is defined by section 63 of the NHPR as the individual, corporate body, institution or organization that conducts or provides funding for a CT. A sponsor is responsible for:

It is mandatory that the sponsor submit REB approval, Qualified Investigator Undertaking and Clinical Trial Site Information forms to the NNHPD prior to commencement of the trial.

Contact for this Application - This is the person who will be faxed the Notice of Authorization and who will be contacted by the NNHPD for specific questions throughout the course of the clinical trial. This person may be an employee of the applicant company or may be contracted from another company on behalf of the applicant, such as a contract research organization.

Senior Official - In the case where the sponsor is a company, institution or organization, this is the person who will represent the sponsor and to whom the Notice of Authorization will be addressed. This should be a senior person, such as a Chief Executive Officer (CEO for a company), Department Head or Centre Director (for institution-investigator initiated CTs). The senior official must sign "Part 7: Attestation" of the Clinical Trial Application and Attestation Form (Appendix 3a).

Senior Medical or Scientific Officer - A scientific or medical officer residing in Canada, representing the sponsor, who is responsible for providing an attestation with respect to the Clinical Trial Application/Amendment at the time of filing, as outlined in Part 7 of the Clinical Trial Application and Attestation Form (Appendix 3a).

Representative in Canada - In the case of a sponsor who is located outside of Canada, this is a person with a Canadian address and to whom the Notice of Authorization is addressed. This person is often the qualified or principal investigator.

Qualified Investigator - This is a medical doctor or a dentist who is entitled to provide health care under the laws of the province where the CT site is located. A dentist may serve as the qualified investigator of dental CTs, but not other types of CTs. A complementary or alternative health care (CAHC) (or a complementary and alternative medicine (CAM)) practitioner can be a principal or co-investigator, but cannot function as a qualified investigator unless he or she is also a licensed physician or dentist. There must be a qualified investigator identified for each CT site, but one qualified investigator may be responsible for more than one site if feasible (i.e., if the locations are relatively close). There must be no more than one qualified investigator for each site. The qualified investigator(s) must sign the Qualified Investigator Undertaking form (Appendix 3c) or a similar document.

The qualified investigator is responsible for:

Principal Investigator - This person is the team leader for the entire CT. They are responsible for coordination of the clinical research, including data collection and analysis. The sponsor or qualified investigator frequently takes on this role.

Co-investigator - This is a member of the CT team designated and supervised by the principal investigator. Co-investigators contribute expertise relevant to the CT.

For clinical research in CAHC it is strongly recommended that a naturopathic doctor, herbalist, homeopathic practitioner, traditional medicine practitioner, or other expert in CAHC be a member of the clinical trial team.

Importer - The individual responsible for bringing an NHP into Canada for use in a CT. Health Canada can issue a Notice of Authorization to a Canadian sponsor. However, if the sponsor is not located in Canada, then an importer located in Canada must be designated by the sponsor using the "Authorization for Third Party to Import the NHP" form (Appendix 3e).

Research Ethics Board - The body of individuals not affiliated with the sponsor, and whose principal mandate is to approve the initiation of, and conduct periodic reviews of biomedical research involving human subjects in order to ensure the protection of the rights, safety and well-being of these subjects and other persons. For each clinical trial site, an REB must review and approve the clinical trial protocol, Informed Consent Form, and clinical trial amendments. Different sites may be subject to different REBs.

The board must have at least five (5) members including the following (note that one member may satisfy more than one of the requirements in the following list):

The REB board member with knowledge of CAHC can serve on the board for just the review of the CT involving the NHP. This individual must be named and their expertise described in the cover letter and should be indicated by checking the appropriate box in the Clinical Trial Application and Attestation Form, Part 2 (Appendix 3a).

The REB representative must sign either the NNHPD REB Attestation form (Appendix 3d) or, the approving REB's similar documentation that meets the same requirement.

Both NNHPD and REB approvals must be obtained by the sponsor prior to commencement of the CT.

Sources of information useful in finding an REB member knowledgeable in CAHC include:

13.0 Contact Information

The envelope containing the Pre-CTA Consultation Package, CTA, CTA-A and CT notifications must be sent to the address below. Please ensure that "Attention: Clinical Trial Unit" appears on the envelope.

Visit our "Contact Us" page.

Glossary

All guidance documents referenced in the glossary are available on the NNHPD's website.

adverse event - any adverse occurrence in the health of a clinical trial subject who is administered an NHP that may or may not be caused by the administration of the NHP, and includes an adverse reaction, a serious adverse reaction and a serious unexpected adverse reaction [Section 63 of the NHPR].

adverse reaction - a noxious and unintended response to an NHP that occurs at any dose used or tested for the diagnosis, treatment or prevention of a disease or for modifying an organic function [Section 1(1) of the NHPR].

biologic - a category of conventional pharmaceuticals as set out on Schedule D to the Food and Drugs Act, prepared from a biological starting or source material, either conventional manufacturing methods, recombinant DNA technology, and/or other novel approaches. Some examples of biologics include vaccines, blood products, living tissues and organs, certain hormones, and certain enzymes.

brand name - a name in English or French, whether or not it includes the name of a manufacturer, corporation, partnership or individual, that is used to distinguish the NHP and under which an NHP is sold or advertised. The brand name may or may not include a trade name.

clinical trial - an investigation in respect of an NHP that involves human subjects and that is intended to discover or verify its clinical, pharmacological or pharmacodynamic effects, to identify any adverse events that are related to its use, to study its absorption, distribution, metabolism and excretion, or to ascertain its safety or efficacy [Section 63 of the NHPR].

clinical trial site - The location(s) where trial-related activities are actually conducted.

common name - for any medicinal or non-medicinal ingredient contained in an NHP, the name by which it is commonly known and is designated in a scientific or technical reference. For example:

common name: Ginger
proper name: Zingiber officinale

The NNHPD recognizes that there may be cases where the common name and proper name will be identical, for example: vitamin C.

comparative bioavailability studies - for the purpose of this document, studies comparing the pharmacokinetics of two NHP formulations in healthy adult volunteers.

comparator - a product which is already licensed in Canada or in those countries in ICH regions (European Union, Switzerland, Japan, and United States) and Australia that is being used within its approved recommended conditions of use as a comparison to the NHP under investigation. Products that are not licensed in the above mentioned countries are considered to be other investigational products which require the evidence for safety, efficacy and quality as described in section 3 of this guidance document.

conditions of use,

conventional pharmaceutical - a drug for human use that falls under the regulation of the TPD (Food and Drug Regulations) and not the NNHPD (NHPR).

date of commencement of a clinical trial - this is defined as the date when the clinical trial site will be ready to enroll subjects in the clinical trial. If known at the time of application, this date should be included in the Clinical Trial Application and Attestation Form.

DIN - the Drug Identification Number is an eight digit numerical code assigned to each drug product marketed under or in accordance with the Food and Drugs Act and the Food and Drug Regulations.

dosage form - the final physical form of the NHP which may be used by the consumer without requiring any further manufacturing. The NNHPD has developed an administrative list for classification of recognized dosage forms, related routes of administrations, synonyms and the applicable definitions. Applicants are not limited to using dosage forms on this list (see Appendix 3 of the Product Licensing Guidance Document).

dose - the amount of finished product in dosage form used for the recommended purpose, including any directions of use. The dose is represented as the amount of dosage units, the frequency of use, and directions for use, if any, by a sub-population group. When the dosage unit is a discrete (separate) dosage form, the dose should be stated as the number of dosage units, such as the number of tablets. For non-discrete dosage forms, such as powder, liquid, ointment and cream, the dosage unit should be stated as a standard equivalent of 5 mL or 15 mL per dose, or as "apply sparingly" or "apply as needed".

duration of use - the time frame during which an NHP will be consumed.

Good Clinical Practices - generally accepted clinical practices that are designed to ensure the protection of the rights, safety and well-being of clinical trial subjects and other persons, and the good clinical practices referred to in section 74 of the NHPR.

import - for the purpose of this document, to bring an NHP into Canada for the purpose of use in a clinical trial.

importer - for the purpose of this document, a person who imports an NHP into Canada for use in a clinical trial.

informed consent - written informed consent, given in accordance with the applicable laws governing consent, must obtained from every person before that person participates in a clinical trial but only after that person has been informed of:

Investigator's Brochure - in respect of an NHP, a document containing the pre-clinical and clinical data on the NHP that are described in section 66(e) of the NHPR.

investigational product - for the purpose of this document, it is the NHP that is to be tested in the clinical trial.

medical device - covers a wide range of health or medical instruments used in the treatment, mitigation, diagnosis or prevention of a disease or abnormal physical condition. Some examples include pacemakers, artificial heart valves and contraceptive devices.

medicinal ingredient - any substance set out in Schedule 1 of the NHPR, or a substance in a homeopathic medicine or traditional medicine that is intended to furnish pharmacological activity or other direct effect in:

natural health product (NHP) - please see Sections 1(1) and 2(2), and Schedules 1 and 2 of the NHPR or section 1.1 of this document for detailed information.

non-medicinal ingredient - any substance added to an NHP to confer suitable consistency or form to the medicinal ingredients. Non-medicinal ingredients may include, but are not limited to, diluents, binders, lubricants, disintegrators, colouring agents and flavours. Some examples of the purposes of non-medicinal ingredients have been included in the "List of Purposes for Non-medicinal Ingredients" (see Appendix 6 of the Product Licensing Guidance Document). The NNHPD has developed a list of non-medicinal ingredients that are generally regarded to be of minimal toxicological concern (refer to the "List of Acceptable Non-medicinal Ingredients" which appears as an appendix to the Evidence for Safety and Efficacy of Finished Natural Health Products Guidance Document). When used under the limitations outlined in the "List of Acceptable Non-medicinal Ingredients", these ingredients are considered to be safe, and will not require further assessment by the NNHPD.

Other types of non-medicinal ingredients may require safety assessment by the NNHPD. Thus, care must be taken to identify the proper submission requirements for non-medicinal ingredients. Applicants are encouraged to submit additional information with their initial CTA, so as to not delay the assessment process.

NPN/DIN-HM - the Natural Product Number or the Drug Identification Number for Homeopathic Medicines is an eight digit numerical code assigned to each NHP approved to be marketed under the NHPR.

observational study - a study where the investigator's do not manipulate the use of, or deliver, an intervention (e.g., do not assign patients to treatment and control groups) nor collect samples from the patients outside of the scope of normal medical practice but only observe patients who are (and sometimes as a basis of comparison, patients who are not) exposed to the intervention, and interpret the outcomes.

phase I - initial safety studies on an NHP, including the first administration of the NHP into humans, usually conducted in healthy volunteers. These trials may be conducted in subjects when administration of the NHP to healthy volunteers is not ethical. Phase I clinical trials are primarily designed to determine the pharmacological actions of the NHP and the side effects associated with increasing doses. Pharmacokinetic studies as well as studies of interactions between health products, are usually considered as phase I trials regardless of when they are conducted during drug development, as these are generally conducted in healthy volunteers. Phase I trials also include trials in which new drugs are used as research tools to explore biological phenomena or disease processes.

phase II - clinical trials to evaluate the efficacy of an NHP in subjects with medical conditions to be treated, diagnosed or prevented and to determine the side effects and risks associated with the NHP. If a new indication for a marketed NHP is to be investigated, then those clinical trials may generally be considered phase II trials.

phase III - controlled or uncontrolled trials conducted after preliminary evidence suggesting efficacy of the NHP has been demonstrated. These are intended to gather the additional information about efficacy and safety that is needed for further risk/benefit assessment of the NHP. In this phase, clinical trials are also conducted in special patient populations (e.g., renal failure patients), or under special conditions dictated by the nature of the NHP and disease.

phase IV - all studies performed after the NHP has been approved by the regulator for the market and related to the approved conditions of use. These studies are often important for optimizing the NHP's use. They may be of any type but must have valid scientific objectives. Commonly conducted studies include safety studies and studies designed to support use under the approved conditions of use, such as mortality and morbidity studies or epidemiological studies.

placebo - an inactive substance (or therapeutic procedure with no intrinsic therapeutic value) that is used in clinical trials for comparison with the active treatment to determine the safety and efficacy of investigational treatments.

potency - the amount per dosage unit of the standardized component that further characterizes the quantity of the ingredient. For information on standardized products, please see the Evidence for Quality of Natural Health Products Guidance Document. For example,

quantity: 500 mg Echinacea purpurea extract
potency: 0.4% echinacoside

product code - the identification code assigned to the product by manufacturer or sponsor.

product monograph - a scientific monograph that is a product-specific document approved by a regulatory authority.

proper name - in reference to medicinal and non-medicinal ingredients, one of the following names:

The following websites may be used in identifying the proper names of ingredients:

protocol - a document that describes the objectives, design, methodology, statistical considerations and organization of a clinical trial.

quantity per dosage unit - the amount of medicinal ingredient per dosage unit (for example, per tablet). Each medicinal ingredient in the product must have a quantity associated with it. The quantity of medicinal ingredient should be based on the proper name of the medicinal ingredient. For example, the quantity of vitamin C in a product should be the quantity of ascorbic acid, not of sodium ascorbate.

The term "potency" in homeopathic medicines is equivalent to quantity when making the declaration to the NNHPD(e.g., 6X, 12CH).

When the ingredient is an extract, the applicant must provide the quantity of the liquid or solid extract per dosage unit, the extraction ratio and the crude dried material equivalent.

The extraction ratio is always expressed as crude dry material to extract, regardless of whether it is a liquid or a solid. For example, a tincture ratio of 1:5 means that 1 g of crude dried material was used to prepare 5 ml of alcoholic extract. In a solid extract, a ratio of 5:1 means that 5 g of crude dried material was used to prepare 1 g of solid extract.

Crude dried material is the material from which the ingredient was extracted. When the extracted ingredient has a potency associated with it (see definition of potency), the crude material equivalent and ratio may not be necessary.

rescue medication - recommended treatments in the event of an overdose, lack of efficacy or adverse event.

risk information - cautions, warnings, adverse reactions and contra-indications associated with the use of the NHP.

route of administration - the method by which the NHP is to be delivered to the body. These routes include, but are not limited to oral, buccal, nasal and topical. As per Schedule 2 of the NHPR, products to be administered by puncturing the dermis are not covered by the NHPR. These products are regulated as drugs, administered by the TPD. The NNHPD has developed a list of recognized routes of administration, with the associated dosage forms (see Appendix 3 of the Product Licensing Guidance Document), to be used to describe the route of administration when completing the CTA form.

scientific monograph - a factual, scientific document on a study substance that, devoid of promotional material, describes the properties, claims, indications, and conditions of use for the study substance, and that contains any other information that may be required for optimal, safe, and effective use of the study substance.

serious adverse reaction - a noxious and unintended response to an NHP 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 [Section 1(1) of the NHPR].

serious unexpected adverse reaction - a serious adverse reaction to an NHP that is not identified in nature, severity or frequency in the risk information set out in the investigator's brochure or on the label of the NHP.

source material - substance from which the medicinal ingredient is derived.

specifications - a description of an NHP that contains the information described in section 44(2) of the NHPR.

study products - investigational product(s), placebo(s), and/or comparator(s) used in the clinical trial.

sub-population group - the group to which the subject NHP is targeted. Most often this will be adults, if there are additional doses, list these as well. For example: children, type 2 diabetics.

synthetic duplicate - a substance that shares an identical chemical structure and pharmacological properties with its natural counterpart. A synthetic duplicate may be manufactured entirely by chemical processes, or by a semi-synthetic process that chemically changes a related starting material that has been extracted or isolated from a plant or a plant material, an alga, a fungus or a non-human animal material. Two examples are the synthetic duplicate of vitamin C and the semi-synthetic ginsenoside Rh2 prepared from betulafolienetriol. Refer to the Evidence for Quality of Finished Natural Health Products Guidance Document for further information on synthetic duplicates and their requirements.

traditional product - is (1) based on the theories, beliefs and experiences indigenous to different cultures, whether explicable or not, used in the maintenance of health, or in the prevention, diagnosis, improvement or treatment of a physical or mental illness and (2) a product for which the traditional use extends back at least fifty years.

use or purpose - the intended beneficial effect of an NHP when used according to the dose, duration of use and route of administration proposed in the CTA.

Appendices

Appendix 1: List of Abbreviations

BGTD
Biologics and Genetic Therapies Directorate
BSE/TSE
bovine spongiform encephalopathy/transmissable spongiform encephalopathy
CAHC
complementary and alternative health care
CAM
complementary and alternative medicine
CT
clinical trial
CTA
clinical trial application
CTA-A
clinical trial application-amendment
DIN
drug identification number
DIN-HM
drug identification number for homeopathic medicine
GCP
good clinical practice
ICH
international conference on harmonization
IRN
information request notice
NHP
natural health product
NNHPD
Natural and Non-Prescription Health Products Directorate
NPN
natural product number
OTC
over the counter
PDN
processing deficiency notice
QOS
quality overall summary
REB
research ethics board
ROD
record of decisions
PDD
Pharmaceutical Drugs Directorate

Appendix 2: Outline of a CTA / CTA-A

Please use the following outline that conforms to the Common Technical Document format. Please note that for a CTA-A only new data should be submitted and other fields in the form can be labelled "No new information". The items marked with an asterisk (*) should be submitted in hard copy and electronic format.

Table - Outline of a CTA / CTA-A
Module Content
1 Administrative / Clinical Information
1.1 Table of Contents (Modules 1-3)
1.2 Application Information
1.2.1 NNHPD Clinical Trial Application Forms
1.2.2 Information on Prior-related Applications
1.2.3* Investigator's Brochure
1.2.4* Protocol Synopsis and Evaluation Review Template (PCERT)
1.2.5* Study Protocol(s)
1.2.6 Informed Consent Document(s)
1.2.7 Clinical Trial Site Information
1.2.8 Canadian Research Ethics Board(s) Refusals
1.2.9 Foreign Refusals
1.2.10 Letters of Access
1.2.11 Other Application-related Information
1.3 Electronic Review Documents
2 Common Technical Document Summaries
2.1 Common Technical Document Table of Contents
2.2 (Not Applicable to Clinical Trials)
2.3* Quality Overall Summary
3 Quality Data (supporting data)
3.1 Table of Contents of Module 3
3.2 Body of Data
3.2.R.1 (Not Applicable to the NNHPD)
3.3 Quality Literature References

Appendix 3: Application Forms

All forms can be found online under Forms.

Appendix 4: Clinical Trial Application and Attestation Form Instructions

Instruction sheet can be found online under Forms.

The Clinical Trial Application and Attestation Form has 7 parts:

For detailed definitions of terms and guidance on completing Clinical Trial Applications (CTAs) and CTA-Amendments (CTA-As), please consult the Clinical Trials for Natural Health Products Guidance Document. The following sections may be particularly useful: Section 3, "Clinical Trial Applications"; Section 6.1, "When Changes to an Approved Clinical Trial Require a CTA-A"; Section 12, "Responsibilities of Those Involved in CTs"; and the Glossary.

All guidance documents and forms referenced in these instructions are available on the Natural and Non-Prescription Health Products Directorate (NNHPD) website.

Part 1: Applicant and Contact Information

Telephone and fax numbers must include the area code and extension, where applicable.

If a P.O. Box is part of the address, the land location must also be provided.

Indicate the language of preference for correspondence by checking the boxes as appropriate. If no preference is indicated, correspondence will default to English. Following approval of the CTA, a Notice of Authorization, addressed to the sponsor, will be faxed to the contact for this application, who may be the sponsor, the sponsor's representative in Canada, or a consultant. Refer to section 12 of the Clinical Trials for Natural Health Products Guidance Document for definitions of sponsor, contact for this application, representative in Canada, and senior official.

Part 2: Research Ethics Board(s)

A Research Ethics Board Attestation must be submitted to the NNHPD prior to commencing the trial if approval is not obtained at the time of application. Research Ethics Boards (REBs) must include a member knowledgeable in complementary or alternative health care (CAHC). This person does not need to be a permanent member of the REB and may be brought in ad hoc.

The NNHPD must be made aware of any REB which has refused the study protocol. Please provide their contact information and reasons for refusal in Module 1 of the CTA, if applicable.

Part 3: Clinical Trial Application Information

Refer to section 3 of the Clinical Trials for Natural Health Products Guidance Document for additional information on submission requirements for CTAs.

Identify the type of application being submitted by checking the appropriate box(es) in section 3A. Definitions of biologic and medical device can be found in the Glossary of the Clinical Trials for Natural Health Products Guidance Document. Please note that if a pharmaceutical, biologic, or medical device is being used in the clinical trial, it must be used according to its approved conditions of use. Please refer to section 1 of the Clinical Trials for Natural Health Products Guidance Document for guidance on whether a CTA should be submitted to the NNHPD.

If the CTA is an amendment, please check the CTA-Amendment box in section 3A and fill out part 4.

The forms listed in section 3C are available online under Forms.

Part 4: Clinical Trial Application - Amendment

Refer to section 4 of the Clinical Trials for Natural Health Products Guidance Document for additional information on submission requirements for CTA-As.

To ensure that the CTA-A is processed as quickly as possible, please provide the submission number of the approved CTA to which changes will be made.

Since amendments must also be approved by the REB, please ensure that Part 2 of the application is completed.

The forms listed in section 4B are available online under Forms.

Part 5: Clinical Trial Site Information

A completed Clinical Trial Site Information Form and a Qualified Investigator Undertaking form must be included for each proposed site known at the time of application. A qualified investigator may oversee more than one site, however, each site may have only one qualified investigator. If the information required to complete these forms is not available at the time of application, these forms must be submitted to the NNHPD prior to the commencement of the trial. If additional CT sites are added after approval has been obtained from the NNHPD, the information must be submitted as a notification to the NNHPD.

Part 6: Study Product Information

Section 1A: Medicinal ingredient(s) of the NHP

[Product Monograph] Indicate whether a product monograph has been submitted (refer to section 3.1.1 of the Clinical Trials for Natural Health Products Guidance Document). The product monograph should be submitted as part of the Investigator's Brochure.

[Common Name] If the common name and proper name are the same, it is acceptable to leave the common name blank.

[Synthetic] See Glossary of the Clinical Trials for Natural Health Products Guidance Document.

[Quantity per Dosage Unit] See Glossary of the Clinical Trials for Natural Health Products Guidance Document.

[Source] Substance from which the medicinal ingredient is derived. See Glossary of the Clinical Trials for Natural Health Products Guidance Document.

Additional copies of this section may be required if there are more than 10 medicinal ingredients in the investigational product or if multiple investigational products are used, where each product has a different medicinal ingredient(s) or the same medicinal ingredient(s), but in different quantities per dosage unit.

Section 1B: Non-medicinal ingredient(s) of the NHP

[Purpose] Some examples of purposes for non-medicinal ingredients can be found in Appendix 6, "Non-medicinal Ingredient List of Purposes", of NNHPD's Product Licencing Guidance Document.

Please note that if a non-medicinal ingredient is found on NNHPD's List of Acceptable Non-medicinal Ingredients (refer to the Evidence for Safety and Efficacy of Finished Natural Health Products Guidance Document), its proper name and source do not need to be provided in the Clinical Trial Application and Attestation Form.

Additional copies may be required if more than 10 non-medicinal ingredients are contained in the investigational product. If multiple investigational products are used, but non-medicinal ingredients are the same, only one copy of this section is needed.

Section 1C: Proposed conditions of use of the NHP according to protocol

[Amount to be taken at one time] Dosage forms of NHPs can be discrete forms, such as tablets and capsules, or non-discrete forms, such as powders and liquids.

As an example of a discrete dosage form, 3 tablets would be written as follows:

No. of dosage units: 3
Dosage unit: tablets

Dosage units of non-discrete dosage forms may be given in grams (g), teaspoons, tablespoons, millilitres (mL), or drops among others. As an example of a non-discrete dosage form, 2 tablespoons would be written as follows:

No. of dosage units: 2
Dosage unit: Tablespoon (15 mL)

Please refer to Appendix 3 of the Product Licencing Guidance Document for further information on dosage forms, dosage units, and routes of administration.

[Risk Information] The risk information from the marketed label, product monograph or Investigator's Brochure is to be provided in the Clinical Trial Application and Attestation Form and the Informed Consent Form. Information from marketed label is required when the investigational product is an approved product (i.e. has an NPN, DIN, or DIN-HM) and is being used in the clinical trial outside its approved conditions of use.

Additional copies of this section may be required if multiple investigational products are used, where each product contains different medicinal ingredients or the same medicinal ingredient(s), but in different quantities per dosage unit.

Section 2: Placebo ingredients

The placebo ingredients will be identified in the same table format as required for the medicinal ingredients. Please refer to the instruction for section 1A of part 6: Medicinal ingredient(s) of the NHP.

The Designated Party Authorization Form can be found online under Forms.

Part 7: Clinical Trial Attestation

Telephone and fax numbers must include the area code and extension, where applicable.

[Senior Medical Officer or Scientific Officer in Canada] See section 12 of the Clinical Trials for Natural Health Products Guidance Document.

[Senior Executive Officer or Department Head] See definition of senior official in section 12 of the Clinical Trials for Natural Health Products Guidance Document.

Appendix 5: Protocol Synopsis and Evaluation Review Template

This form can be found online under Forms.

Protocol Synopsis & Evaluation

Date Submitted HPB Use Only

Submission Number HPB Use Only

Trial Title and Number

Background / Rationale

Trial Objectives

Study Design

Study Duration

Number of Sites (inside and outside of Canada)

List of Investigators

Sample Size

Patient Population

Inclusion Criteria

Exclusion Criteria

NHP Formulation

Dosage Regimen

Prestudy Screening and Baseline Evaluation

Treatment Visit

Premature Withdrawal/Discontinuation Criteria

Rescue Medication

Washout Period

Concomitant Medication

Variables to be Assessed

Efficacy Analysis

Safety Analysis

Statistical Analysis

Current Problems/Concerns

Patient Consent Form Evaluation
Requirement Evaluation Status
Full Disclosure of Risk   Acceptable
  Requires Revision
Clarity of Language   Acceptable
  Requires Revision
Description of Procedure   Acceptable
  Requires Revision
Confidentiality for Patient   Acceptable
  Requires Revision
Lack of Bias   Acceptable
  Requires Revision
Placebo and/or Comparator Disclosure   Acceptable
  Requires Revision
Investigatory Brochure Evaluation
Requirement / Version Dated: Evaluation Status
Accuracy of Information   Acceptable
  Requires Revision
Rationale for Investigation   Acceptable
  Requires Revision
Completeness   Acceptable
  Requires Revision
Numerical Data   Acceptable
  Requires Revision
Tabulation of Actual Results   Acceptable
  Requires Revision
Side Effects   Acceptable
  Requires Revision
Summary of ADR: Deaths, Serious, Other   Acceptable
  Requires Revision
Information on Patient Exposure,
Duration of Study, Location of Study, NHP Dosage		   Acceptable
  Requires Revision
Dosage Formulation   Acceptable
  Requires Revision

Appendix 6: Informed Consent Form Guidelines

Please include the following information (if applicable):

  1. Title
  2. Purpose of the clinical trial
  3. Design of the clinical trial (including definitions of randomized, double blinded, and parallel or cross-over design, as well as the probability of random assignment to each treatment group)
  4. Reason why the subject has been chosen to participate
  5. Description of the composition and direction of use of the study product(s) (investigational product, placebo, comparator)
  6. Duration of the clinical trial
  7. Duration of subject's involvement
  8. What will occur during the clinical trial, specifically:
    • Study procedures
    • Treatment visits
    • Subject's responsibilities (before, during and after trial)
  9. Risks/disadvantages of participating in the clinical trial
  10. Side effects to the investigational product, placebo and comparator
  11. Contraindicated medications (prescription and non-prescription) to the investigational product, placebo and comparator
  12. A statement indicating there may be unknown risks with taking the investigational product
  13. Benefits/advantages of participating in the clinical trial
  14. Alternative treatment options
  15. Subjects will be informed should new information become available on the investigational product
  16. A statement informing subjects that investigators must be informed when a new medication (including NHPs) is taken during the clinical trial
  17. Participation is voluntary and that subjects may drop out at any time without consequence
  18. Subjects will not be giving up any legal rights by participating in the clinical trial
  19. What the subject should do if they experience an adverse event and how the subject should report them and to whom
  20. Circumstances under which the subject could be removed from the clinical trial
  21. How confidential information will be treated
  22. What will happen to the subject's information when the clinical trial has ended
  23. Who is organizing and funding the clinical trial
  24. Who has approved the clinical trial
  25. Contact information
  26. Please provide a place for the subject to initial on every page

Note: Subjects are to receive their own copy of the signed consent form to keep.

Appendix 7: Quality Overall Summary-NHP (CTA - Phases I/II/III) Template

This form can be found online under Forms.

Module 2.3: Quality Overall Summary - NHPs
Introduction

(a) Summary of investigational finished product(s) information (copy table as needed):

(b) Excerpt from Protocol Synopsis:

(c) Information on the comparator product:

(d) If the information in any section (or subsection) has previously been submitted (in its entirety, without changes), and approved by Health Canada, do not resubmit that section. Provide the following information on the cross- referenced submission(s):

Provide the following information on the cross- referenced submission(s):
Section
(and subsections)		 Cross-Referenced
Submission Name		 File Number and
Control Number		 Date
Approved
Medicinal
Ingredient		      
Finished Natural
Health Product		      

Note: Based on the NHP substances set out in Schedule 1 of the NHPR, the medicinal ingredients have been divided into three categories as indicated below. To prepare the chemistry and manufacturing information for the medicinal ingredient(s) used in your study product, please select a category (from Part A) that applies to your product. If more than one category applies (e.g., in a combination product), please complete the necessary combination of categories. To prepare the chemistry and manufacturing information for the finished product, please complete Part B. The template in Part C for the Finished NHP Specifications is also required. If any specific section does not apply to your product, please indicate as "Not Applicable". Sections that are "Not applicable" should not be deleted and should be accompanied by an explanatory note describing the reasons for the inapplicability. For more detailed information on the category of ingredients and their requirements, please see the Evidence for Quality of Finished Natural Health Products Guidance Document.

Part A: Chemistry & Manufacturing Information of Medicinal Ingredient(s)
The following are the categories of substances from Schedule 1 of the NHPR for which specific quality requirements are described in detail below.

Category I: Plant, Plant material, Alga, Fungus, Bacterium, Non-Human Animal Material

Category II: Isolate, Synthetic Duplicate, Non-Standardized and Standardized Extract, Amino Acid, Essential Fatty Acid, Vitamin, Minerals

Category III: Probiotics

Category I - Plant, Plant material, Alga, Bacterium, Fungi, Non-Human Animal Material

2.3.S Medicinal Ingredient(s)

2.3.S.1 General Information

2.3.S.1.1 Nomenclature

  1. Latin Binomial Name (genus and, if any, its specific epithet):
  2. Common name:
  3. Other (e.g., strain number for microbial cultures):

2.3.S.1.2 Structure

  1. Structural formula, including relative and absolute stereochemistry:
  2. Molecular formula:
  3. Molecular mass:

2.3.S.1.3 General Properties

  1. Physical description (e.g., organoleptic, colour, shape):
  2. Part of the Plant used (e.g., leaf, stem):
  3. Part of the non-human animal used (e.g., cartilage):
  4. Other relevant information:

2.3.S.2 Manufacturing Information

2.3.S.2.1 Manufacturer(s)

  1. Name, address, and responsibility of each manufacturer, including contractors (if any) and each proposed production site or facility involved in the manufacturing of the batches to be used in this clinical trial:
  2. List of referenced NHP or Drug Master Files (NHP-MFs or DMFs) and NHP-MF or DMF Numbers (copies of NHP-MF or DMF letters of access should be located in Module 1):

2.3.S.2.2 Description of Manufacturing Process and Process Controls

  1. Manufacturing information is not required for plant, algal, fungal, bacterial and non-human animal material and their non-standardized extracts. However, for all non-standardized extracts a list of solvents used in the extraction is required:

2.3.S.3 Characterisation

2.3.S.3.1 Identification of Medicinal Ingredient

  1. List of spectroscopic methods and/or chromatographic fingerprinting studies performed (e.g., UV HPLC, TLC, and GC) (for plant, plant material, alga, bacterium and fungus):
  2. If applicable, DNA fingerprinting studies and summary of the interpretation (e.g. non-human animal material)
  3. Summary of studies performed to identify Foreign Matter (e.g., sand, dirt, insect parts, glass and metal) and Acid-insoluble Ash, if applicable:
  4. Summary of studies performed to identify water content (for plant, plant material, and their non-standardized extracts):
  5. Other identification evidence such as phenotypic and genotypic identification methods (e.g. comparison of plant sample with herbarium specimen, microscopic characterization of bacterium, DNA fingerprint):

2.3.S.3.2 Impurities

a. Identification of potential and actual chemical impurities:

List of possible chemical and microbial contaminants. If more than one batch used, complete a table for each batch:
Type of Contaminant Test Test Method Used Medicinal Substance Tolerance Limits Acceptable NNHPD's Tolerance Limits
Chemical Contaminants Arsenic     < 0.14 (µg /kg b.w./day)
Cadmium     < 0.09 (µg /kg b.w./day)
Lead     < 0.29 (µg /kg b.w./day)
Total mercury     < 0.29 (µg /kg b.w./day)
PCD&PCDF     Dioxins < 2 pg/kg/b.w./day;
PCBs     PCBs < 0.13 µg/kg/b.w./day
Mycotoxins     Aflatoxins:< 0.02 µg/g of substance
Loss on Drying     Pharmacopoeial Limits
Foreign Matter     Pharmacopoeial Limits
Ash Content     Pharmacopoeial Limits
Pesticides     Pharmacopoeial Limits
Solvent residues     ICH or pharmacopoeial limits
Microbial Contaminants Contaminating fungus     For acceptable NNHPD microbial contaminant tolerance limits for each category of products, refer to Appendix 2, Table 1 in the Evidence for Quality of Finished Natural Health Products guidance document
Total Aerobic Count    
Escherichia coli    
Salmonella spp.    
Staphylococcus aureus    
Enterobacter spp.    
Pseudomonas aeruginosa (if product is in <50% aqueous ethanol)    

Note: Please duplicate this table for each medicinal ingredient used in your study product

2.3.S.4 Control of the Medicinal Ingredient

2.3.S.4.1 Quantity

a. Quantity requirements for plant, plant material, alga, fungus, bacterium, non-human animal material:
Medicinal Ingredient Name of Medicinal Ingredient (s) Test Method Used Medicinal Ingredient Tolerance Limits Acceptable NNHPD's Tolerance Limits
Plant or Plant Material       80-120%
Alga       80-120%
Fungus       80-120%
Bacterium       80-120%
Non-Human Animal Material       80-120%

2.3.S.4.4 Batch Analyses

a. Description of the batches to be used in this clinical trial:
Batch Number Batch Size Date and
Site of Production		 Use (e.g., clinical)
       
       
       
       
       

2.3.S.6 Container Closure System

  1. Description of the container closure system(s) for the storage and shipment of the medicinal substance:

2.3.S.7 Stability

2.3.S.7.1 Stability Summary and Conclusions

  1. Summary of stability studies to support this clinical trial (e.g., studies conducted, protocols used, duration of test, results obtained):

2.3.S.7.2 Post-approval Stability Protocol and Stability Commitment

  1. If full long-term stability data are not available at the time of submission, provide the stability protocol, accelerated stability data and a commitment for the continued monitoring of the medicinal substance stability according to the protocol for the duration of the clinical trial (i.e., so that if the product degrades below the tolerance limit during the trial, more product can be taken out of cold storage. If a new batch needs to be used, sponsor should notify NNHPD as a notification in order to maintain the same quality and specifications):

2.3.S.7.3 Stability Data

  1. The actual stability results (i.e., raw data) used to support the clinical trial:

Category II: Isolate, Synthetic Duplicate, Non-Standardized and Standardized Extract, Amino Acid, Essential Fatty Acid, Vitamin, Minerals

2.3.S. MEDICINAL INGREDIENT(S)

2.3.S.1 General Information

2.3.S.1.1 Nomenclature

  1. Proper Name:
  2. Common Name:
  3. If an isolate or a standardized extract, proper name of source organism:
  4. If an isolate or a standardized extract, common name of source organism:
  5. Company or laboratory code:
  6. Other non-proprietary name(s) (e.g., national name, USAN, BAN
  7. Chemical Abstracts Service (CAS) registry number, if available:

2.3.S.1.2 Structure

  1. Structural formula, including relative and absolute stereochemistry:
  2. Molecular formula and/or molecular mass:

2.3.S.1.3 General Properties

  1. Physical description (e.g., appearance, colour, taste, smell, physical state):
  2. pH and pKa values:
  3. Other relevant information:

2.3.S.2 Manufacturing Information

2.3.S.2.1 Manufacturer(s)

  1. Name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in the manufacturing of the batches to be used in this clinical trial:
  2. List of referenced NHP or Drug Master Files (NHP-MFs or DMFs) and NHP-MF or DMF Numbers (copies of NHP-MF or DMF letters of access should be located in Module 1):

2.3.S.2.2 Description of Manufacturing Process and Process Controls

  1. Flow diagram of the extraction, isolation and/or synthetic process(es):
  2. Brief narrative description of the manufacturing process(es), e.g. temperature, solvents used, and reagents:

2.3.S.2.3 Control of Materials

  1. For medicinal ingredient(s) either obtained from non-human animal sources or processed using materials that present a risk of transmitting BSE/ TSE agents (e.g., ruminant origin), a completed Animal Tissue Form (ATF) must be submitted ; see Appendix 3 of the Clinical Trials for Natural Health Products Guidance Document.

2.3.S.3 Characterization

2.3.S.3.1 Characterization of Chemical Identity

  1. List of studies performed (e.g., IR, UV, NMR, MS, elemental analysis or HPLC, GC, with MS or UV-diode array detector) and summary of the interpretation of evidence of structure:
  2. Discussion on the potential for isomerism and identification of stereochemistry (e.g., geometric isomerism, number of chiral centres and configurations):
  3. Other characteristics (product specific):

2.3.S.3.2 Impurities

Identification of potential and actual impurities arising from the extraction, isolation, synthesis, manufacture, fermentation and/or degradation. If more than one batch used, complete a table for each batch :
Process Related Impurities Chemical Name or Structure Test Method
(e.g. HPLC)		 Limit of Detection
(e.g. %)
Starting material impurities      
By-products      
Intermediates      

Chiral Impurities

      
Residual Solvents      
Residual Reagents      
Other      

Note: Please add to the above table other types of impurities if applicable.

2.3.S.4 Control of the Medicinal Ingredient

2.3.S.4.1 Specification

Specification for the medicinal substance:
Assessment Criteria Test Test Method Medicinal Ingredient Results / Tolerance Limits NNHPD's Accepted Tolerance Limit
Identity Physical Description (Organoleptic)      
Chemical Identity (HPLC)      
Assay (Purity/impurity profile)      
Loss on Drying      
Purity Chemical Contaminants Arsenic     < 0.14 (µg /kg b.w./day)
Cadmium     < 0.09 (µg /kg b.w./day)
Lead     < 0.29 (µg /kg b.w./day)
Total Mercury     < 0.29 (µg /kg b.w./day)
Specific Toxins (when applicable) PCD, PCDD, PCDF     Dioxins < 2 pg/kg/b.w./day;
PCBs     PCBs < 0.13 µg/kg/b.w./day
Pesticides (when applicable)     Pharmacopoeial limits
Solvent Residues (when applicable)     ICH or pharmacopoeial limits
Mycotoxins     Aflatoxins:< 0.02 µg/g of substance
Microbial Contaminants Contaminating fungus     For acceptable NNHPD microbial contaminant tolerance limits for each category of products, refer to Appendix 2, Table 1 in the Evidence for Quality of Finished Natural Health Products guidance document
Total Aerobic Count    
Escherichia coli    
Salmonella spp    
Staphylococcus aureus    
Enterobacter spp.    
Pseudomonas aeruginosa (if product is in < 50% aqueous ethanol)    
Quantity/Potency Quantity of the Medicinal Ingredient per dosage unit     For acceptable NNHPD quantity tolerance limits for each category of products, refer to section 2.4.3 in the Evidence for Quality of Finished Natural Health Products guidance document

2.3.S.4.4 Batch Analyses

a. Description of the batches to be used in this clinical trial:
Batch Number Batch Size Date and
Site of Production		 Use (e.g., clinical)
       
       
       
       

2.3.S.6 Container Closure System

  1. Description of the container closure system(s) for the storage and shipment of the medicinal substance:

2.3.S.7 Stability

2.3.S.7.1 Stability Summary and Conclusions

  1. Summary of stability studies to support this clinical trial (e.g., studies conducted, protocols used, duration of test, results obtained). If not available at time of submission, provide accelerated stability data:

2.3.S.7.2 Post-approval Stability Protocol and Stability Commitment

  1. If full long-term stability data are not available at the time of submission, provide the stability protocol, accelerated stability data and a commitment for the continued monitoring of the medicinal substance stability according to the protocol for the duration of the clinical trial (i.e., so that if the product degrades below the tolerance limit during the trial, more product can be taken out of cold storage. If a new batch needs to be used, sponsor should notify NNHPD as a notification in order to maintain the same quality and specifications):

2.3.S.7.3 Stability Data

  1. The actual stability results (i.e., raw data) used to support the clinical trial:

Category III - Probiotics

2.3.S Medicinal Ingredient(s)

2.3.S.1 General Information

2.3.S.1.1 Nomenclature

  1. Genus, specific epithet, strain:
  2. Common name(s):

2.3.S.1.3 General Properties

  1. Physical description (e.g., appearance, pellet, powder, colour):
  2. Other relevant information:

2.3.S.2 Manufacturing Information

2.3.S.2.1 Manufacturer(s)

  1. Name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in the manufacturing of the batches to be used in this clinical trial:
  2. List of referenced NHP or Drug Master Files (NHP-MFs or DMFs) and NHP-MF or DMF Numbers (copies of NHP-MF or DMF letters of access should be located in Module 1):

2.3.S.2.2 Description of Manufacturing Process and Process Controls

  1. Flow diagram of the mother culture preparation and fermentation conditions used:
  2. Brief narrative description of the manufacturing process(es). In addition to this information, data provided for a medicinal ingredient produced by fermentation should include source and type of micro-organism used, composition of media, precursors, reaction conditions (e.g., time, temperature, rate of aeration etc.), name and composition of preservatives, if any:

2.3.S.2.3 Control of Materials

  1. For medicinal ingredient(s) processed using materials that present a risk of transmitting BSE/ TSE agents (e.g., ruminant origin), a completed Animal Tissue Form (ATF) must be submitted see Appendix 3 of the Clinical Trials Guidance Document.

2.3.S.3 Characterization

2.3.S.3.1 Characteristics of the culture

  1. Phenotypic and/or genotypic identification:
  2. Other characteristics:

2.3.S.3.2 Impurities

  1. Identification of microbial impurities:

    1. List of related microbial impurities, if applicable. If more than one batch used, complete a table for each batch:
List of related microbial impurities
Microbial Contaminant(s) Test Method Used Medicinal Ingredient Tolerance Limits NNHPD's Acceptable Tolerance Limits
       
       
       
       
       

2.3.S.4 Control of the Medicinal Ingredient

2.3.S.4.1 Total Viable Count

a. Total viable count requirements for the probiotic culture(s):
Probiotic Culture(s) Test Method Used Test Limits (CFU/g or CFU/ml) NNHPD's Acceptable Tolerance Limits
      80-300%
       
       
       
       

2.3.S.4.4 Batch Analyses (name, manufacturer, if applicable):

a. Description of each batch to be used in this clinical trial:
Batch Number Batch Size Date and
Site of Production		 Use (e.g., clinical)
       
       
       
       

2.3.S.7 Stability

2.3.S.7.1 Stability Summary and Conclusions

  1. Summary of stability studies to support this clinical trial (e.g., studies conducted, protocols used, duration of test, results obtained). If not available at time of submission, provide accelerated stability data:

2.3.S.7.2 Post-approval Stability Protocol and Stability Commitment

  1. If full long-term stability data are not available at the time of submission, provide the stability protocol, accelerated stability data and a commitment for the continued monitoring of the medicinal substance stability according to the protocol for the duration of the clinical trial (i.e., so that if the product degrades below the tolerance limit during the trial, more product can be taken out of cold storage. If a new batch needs to be used, sponsor should notify NNHPD as a notification in order to maintain the same quality and specifications):

2.3.S.7.3 Stability Data

  1. The actual stability results (i.e., raw data) used to support the clinical trial:

Part B: Chemistry & Manufacturing Information of the Finished NHP

2.3.P Finished NHP

2.3.P.1 Description and Composition of the Finished Product

  1. Description of the dosage form:

  2. Composition of the dosage form:
    1. Composition - list of all medicinal and non-medicinal ingredients of the dosage form, and their amounts on a per unit basis (including overages, if any):
Medicinal and non-medicinal ingredients of the dosage form
Medicinal and Non-Medicinal Ingredients and Quality Standard (and grade, if applicable) Intended Functions For NMIs Quantity/Dosage Unit
Quantity per Unit %
Medicinal Ingredients:      
Non-Medicinal Ingredients:      
Total      

c. Description of accompanying reconstitution diluent(s), if
applicable:

d. Quantitative list of the components of the placebo samples to be used in this clinical trial:
Name of Each Component of the Placebo Quantity of Each Component in the Placebo
   
   
Total Amount  

2.3.P.2 Formulation Development

  1. or a new formulation (new combination, standardized extract, or new dosage form such as transdermal patch) provide a rationale on the development:
  2. For sterile, reconstituted products, provide a summary of compatibility studies with diluents/containers:

2.3.P.3 Manufacturing Information

2.3.P.3.1 Manufacturer(s)

  1. Name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in the manufacturing of the batches to be used in this clinical trial:
  2. List of referenced NHP or Drug Master Files (NHP-MFs or DMFs) and NHP-MF or DMF Numbers (copies of NHP-MF or DMF letters of access should be located in Module 1:

2.3.P.3.2 Batch Formula

a. List of all components of the dosage form to be used in the manufacturing process, and their amounts on a per batch basis (including overages, if any):
Quantity per Dosage Unit (strength)  
Batch Size(s) (number of dosage units)  
Date of Manufacture  
Component and Quality Standard (and grade, if applicable) Quantity Per Batch
Medicinal Ingredient:  
   
Non-Medicinal Ingredient:  
   
Total  

Note: If more than one batch produced (e.g., additional lots of finished product or different strengths), duplicate table as needed.

2.3.P.3.3 Description of Manufacturing Process and Process Controls

  1. Flow diagram of the manufacturing process:
  2. Narrative description of the manufacturing process and process parameters:
  3. For sterile/pasteurized products, details and conditions of sterilization and/or lyophilization :

2.3.P.4 Control of Non-medicinal Ingredients

  1. Confirmation if the non-medicinal ingredients (NMI) used are included in the List of Acceptable Non-medicinal Ingredients:

    If not, please provide the following information:
  2. List and summary of the information of NMIs that are of non-human animal origin (including country of origin):
  3. For NMIs obtained from sources that are at risk of transmitting BSE/ TSE agents, a letter of attestation (with supporting documentation) should be provided confirming that the material is not from a BSE/TSE affected country/area.
  4. Confirmation that none of the non-medicinal ingredients which appear in the finished product are prohibited for use in drugs by the Canadian Food and Drug Regulations:

2.3.P.4.1 Novel Non-medicinal Ingredients

  1. Summary of the details on the manufacture, characterization, and controls, with cross references to supporting safety data (nonclinical and/or clinical) on novel NMIs (e.g., those used for the first time in the finished product or by a new route of administration):

2.3.P.5 Control of Finished NHP

2.3.P.5.1 Specification(s)

Specification(s) for the finished product:
Assessment Criteria Test Test Method Medicinal Ingredient Results / Tolerance Limits NNHPD's Accepted Tolerance Limit
Identity Physical Description (Organoleptic)      
Chemical Identity (HPLC)      
Assay (Purity/impurity profile)      
Disintergration and/or Dissolution     45 min (uncoated)
60 min (plain coated)
Particle Size Distribution, (if applicable, e.g. for tea)      
Purity Chemical Contaminants Arsenic     < 0.14 (µg /kg b.w./day)
Cadmium     < 0.09 (µg /kg b.w./day)
Lead     < 0.29 (µg /kg b.w./day)
Total Mercury     < 0.29 (µg /kg b.w./day)
Specific Toxins (when applicable) PCD, PCDD, PCDF     Dioxins < 2 pg/kg/b.w./day;
PCBs     PCBs < 0.13 µg/kg/b.w./day
Pesticides (when applicable)     Pharmacopoeial limits
Solvent Residues (when applicable)     ICH or pharmacopoeial limits
Mycotoxins     Aflatoxins:< 0.02 µg/g of substance
Microbial Contaminants Contaminating fungus     For acceptable NNHPD microbial contaminant tolerance limits for each category of products, refer to Appendix 2, Table 1 in the Evidence for Quality of Finished Natural Health Products guidance document
Total Aerobic Count    
Escherichia coli    
Salmonella spp    
Staphylococcus aureus    
Enterobacter spp.    
Pseudomonas aeruginosa (if product is in < 50% aqueous ethanol)    
Quantity/Potency Quantity of the Medicinal Ingredient per dosage unit     For acceptable NNHPD quantity tolerance limits for each category of products, refer to section 2.4.3 in the Evidence for Quality of Finished Natural Health Products guidance document

Note: In this table all information that is required to support finished product specifications should be included.

2.3.P.5.4 Batch Analyses

a. Description of the batches to be used in this clinical trial:
Strength (Quantity / Dosage Unit) Batch Number Batch Size Date and
Site of Production		 Use (e.g., clinical)
         
         
         
         

2.3.P.5.5 Characterisation of Impurities

Information on the characterization of impurities derived from the processing of the finished product, interaction between medicinal and non-medicinal ingredients, and/or other medicinal ingredient related impurities.

2.3.P.7 Container Closure System

  1. Description of the container closure systems, container size or volume:
  2. Materials of construction of each primary packaging component:
  3. For sterile products, details of washing, sterilization, pasteurization, depyrogenation procedures or other process for container closures, e.g. for ophthalmic use.

2.3.P.8 Stability

2.3.P.8.1 Stability Summary and Conclusions

  1. Summary of stability studies to support this clinical trial (e.g., studies conducted, protocols used, duration of test, results obtained):

    1. Description of stability study:
Stability Summary and Conclusions
Batch Number Time Interval Storage Conditions (°C, % RH, light) Description of Product Strength (Quantity per Dosage Unit)/Potency of Product
         
         
         

ii. Summary and discussion of stability study results:

b. Proposed storage conditions and shelf life:

2.3.P.8.2 Post-approval Stability Protocol and Stability Commitment

  1. If full long-term stability data are not available at the time of submission, provide the stability protocol, accelerated stability data and a commitment for the continued monitoring of the medicinal substance stability according to the protocol for the duration of the clinical trial (i.e., so that if the product degrades below the tolerance limit during the trial, more product can be taken out of cold storage. If a new batch needs to be used, sponsor should notify NNHPD as a notification in order to maintain the same quality and specifications):

2.3.P.8.3 Stability Data

  1. The actual stability results (i.e., raw data) used in support of this clinical trial:

Part C: Finished Natural Health Product Specification Template

Name of the Finished Product:
Name of Manufacturer of Finished Product:
Batch Number:

Specification(s) for the finished product:
Assessment Criteria Test Test Method Medicinal Ingredient Results / Tolerance Limits NNHPD's Accepted Tolerance Limit
Identity Physical Description (Organoleptic)      
Chemical Identity (HPLC)      
Assay (Purity/impurity profile)      
Disintergration and/or Dissolution     45 min (uncoated)
60 min (plain coated)
Particle Size Distribution, (if applicable, e.g. for tea)      
Purity Chemical Contaminants Arsenic     < 0.14 (µg /kg b.w./day)
Cadmium     < 0.09 (µg /kg b.w./day)
Lead     < 0.29 (µg /kg b.w./day)
Total Mercury     < 0.29 (µg /kg b.w./day)
Specific Toxins (when applicable) PCD, PCDD, PCDF     Dioxins < 2 pg/kg/b.w./day;
PCBs     PCBs < 0.13 µg/kg/b.w./day
Pesticides (when applicable)     Pharmacopoeial limits
Solvent Residues (when applicable)     ICH or pharmacopoeial limits
Mycotoxins     Aflatoxins:< 0.02 µg/g of substance
Microbial Contaminants Contaminating fungus     For acceptable NNHPD microbial contaminant tolerance limits for each category of products, refer to Appendix 2, Table 1 in the Evidence for Quality of Finished Natural Health Products guidance document
Total Aerobic Count    
Escherichia coli    
Salmonella spp    
Staphylococcus aureus    
Enterobacter spp.    
Pseudomonas aeruginosa (if product is in < 50% aqueous ethanol)    
Quantity/Potency Quantity of the Medicinal Ingredient per dosage unit     For acceptable NNHPD quantity tolerance limits for each category of products, refer to section 2.4.3 in the Evidence for Quality of Finished Natural Health Products guidance document

Signature:

Date:

Note: For any revisions in the product specifications, resubmit a revised copy of this template.

Appendix 8: Adverse Reaction Report Form for Clinical Trials

This form can be found online under Forms.

Adverse Reaction Report Form For Clinical Trials

Page details

Date modified: