Final Response to the Natural Health Products Program Advisory Committee

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.

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Report 1-Standards of Evidence for Non-Traditional Natural Health Products

(PDF Version - 520 K)

July 2010

This document describes the Natural Health Products Directorate's (NHPD) final response to the Natural Health Products Program Advisory Committee's report of January 26, 2010 titled "Report 1 - Standards of Evidence for Non-Traditional Natural Health Products".

This document supersedes the NHPD's preliminary response dated February 15, 2010.

Table of Contents

NHPD Response

Natural Health Products Program Advisory Committee (NHP-PAC)

The Natural Health Products Program Advisory Committee (NHP-PAC) provides views, advice and recommendations on issues under federal responsibility regarding the regulation of the safety, quality and efficacy of natural health products for sale in Canada.

The NHP-PAC Working Group #1 on Standards of Evidence was tasked with preparing a report containing recommendations related to the Standards of Evidence for Non-Traditional Natural Health Products.

Report 1: Standards of Evidence for Non-Traditional Natural Health Products

The NHP-PAC presented its Report 1: Standards of Evidence for Non-Traditional Natural Health Products to the NHPD on January 26, 2010. This report included 33 recommendations ensuing from the committee deliberations, including rationales and the range of views/support for each of the recommendations.

A preliminary response for each of the recommendations was posted on the NHPD website on February 15, 2010 and discussed at the NHP-PAC meeting on March 22-23, 2010. At the June 14, 2010 meeting, the NHPD presented a more fulsome response to the recommendations, the result of which is the following report.

NHPD Response to the Recommendations

The NHPD is in agreement with the vast majority of the NHP-PAC recommendations. A critical aspect of this concurrence is based on a shared understanding that the level of the claim, benefit to the consumer and the risk to the consumer should influence the standard of evidence required to support a natural health product. As such, the NHPD will continue to apply a risk-based approach to the assessment of natural health products licence applications, supported by the continued development and implementation of process improvements and pre-cleared information.

The NHPD has committed to updating the Evidence for the Safety and Efficacy of Finished Natural Health Products guidance document and this update will follow a careful consideration of the NHP-PAC recommendations related to the standards of evidence. As part of this review, the NHPD will provide guidance on acceptable types of data including the use of:

  • international market experience (Recommendation 6)
  • animal studies (Recommendation 9)
  • observational data (Recommendation 11)
  • qualitative studies (Recommendation 12)
  • validated surrogate markers and end-points (Recommendation 13)
  • level IV studies and secondary data (Recommendation 14)
  • expert opinion reports (Recommendation 15)
  • traditional and non-traditional evidence for combination products (Recommendation 18 and 19)

The NHPD will also review and seek clarification of the decision tree submitted by PAC members and the outcomes will be reflected within NHPD guidance documents. (Recommendation 5, 21)

The NHPD is pleased to note that many of the PAC recommendations are supportive of NHPD initiatives already in place or underway. The NHPD is committed to providing applicants with clear, informative and timely information, through updates on pre-cleared information, information request notices, access to Safety and Efficacy Assessment Reports, pre-submission meetings, developing and updating guidance documents, and educational workshops. (Recommendations 4, 7, 27) An Application Management Policy has been developed, which includes instructions on access to reports, as well a discussion of NHPD's proposed performance standards. (Recommendation 7, 8)

Further the NHPD has made significant progress on issues involving extracts (Recommendation 16), fungal enzymes (Recommendation 29), and combination products with sub-therapeutic ingredients (Recommendation 30).

A more detailed response to all 33 recommendations can be found below.

Appendix A: Recommendations and NHPD Responses

Recommendation 1

The Evidence for the Safety and Efficacy of Finished Natural Health Products Guidance Document (the Guidance Document) should be amended to provide more clarity on the definition of risk. Risk should be defined according to both "manufacturing risk" (what is in the product) and "situational risk" (its recommended conditions of use), according to defined standards.

Recommended by: All PAC members

Rationale/Discussion: The risk level of a natural health product is tied to the level of evidence and can be described as manufacturing risk (Good manufacturing Practices) and situational risk (ingredient, consumer). The evidence requirements for both efficacy and safety are based on the overall risk-benefit of a product. Risk-benefit ratio should be predictable based on defined standards.

Response to Recommendation 1: Agree

The NHPD agrees that the level of the claim and the risk to the consumer should influence the standard of evidence required to support a natural health product. The NHPD will continue to apply a risk-based approach to the assessment of NHP licence applications.

Recommendation 2

The Guidance Document should be amended to provide guidance and clarity about the minimum amount and robustness of evidence required to seek Health Canada approval and communicate evidence requirement changes to stakeholders. Other recommendations in this report provide further specificity to this recommendation. All updates are promptly incorporated into the guidance document and disseminated to stakeholders.

Recommended by: All PAC members

Rationale/Discussion: The evidence requirements for both efficacy and safety are based on the overall risk-benefit of a product. This risk-benefit ratio should be predictable based on defined standards; applicants need specific guidelines provided in advance to determine the exact licence requirements for their products. Guidance (predictive value) on the type of evidence required for the level of health claim is needed for product licence applicants, e.g., how much and what kind of evidence is needed for non-traditional products.

Response to Recommendation 2: Agree

The NHPD is examining the various PAC proposals and recommendations related to the standards of evidence required for market authorization and will incorporate these into a revised Evidence for the Safety and Efficacy of Finished Natural Health Products guidance document. The NHPD endeavors to update guidance documents and inform stakeholders in a timely manner, including by e-mailing applicants where web-based updates are delayed.

Recommendation 3

The increasing role of consumers consulting their health care professional should be acknowledged and encouraged. As well, Health Canada should inform health care professionals, where possible, when their patient files an adverse event report with Health Canada to support follow-up with patients and also to support comprehensiveness and accuracy of adverse reactions information received. This relates to the awareness/information provided to health care Professionals.

The adverse reaction categories are: causal, not causal, not able to determine. Suggestion that those Health Canada reviewers and policy analysts who understand the therapeutic aspects of the products be involved in the adverse reaction data analysis from NHPD to:

  • link the approval/review context and understanding of consumer behaviour;
  • provide a mechanism to share knowledge/educate on natural health products
  • increase awareness and information on adverse reaction reporting, with information targeting specific stakeholder groups to address specific needs.

It is proposed that this recommendation be brought forward to the Marketed Health Products Directorate for implementation.

Recommended by: All PAC members

Rationale/Discussion: This should lead to greater post-market surveillance, therefore greater safety for the consumer (supports rapid response). This is not a recommendation to change the Standards of Evidence Supports unique nature of health care professional responsibility and follow-up with clients - Adverse event may be an expected outcome of treatment (aggravation of symptoms/conditions is a desired response).

Response to Recommendation 3: Agree

As recommended, this issue has been brought to the attention of the Marketed Health Products Directorate for further assessment.

Recommendation 4

The NHPD should provide clear feedback in Information Request Notices that are issued when a reference submitted by an applicant is not accepted (e.g., an Expert Opinion Report, previous market experience, textbook - see comment Recommendation #10). Where possible, the NHPD should outline which section of the reference was problematic as well as offer potential solutions (e.g., Pre-Cleared Information). The NHPD should ensure that the rationales used in Information Request Notices are up-to-date.

Recommended by: All PAC members

Rationale/Discussion: When an applicant receives an Information Request Notice noting the insufficiency of a particular evidence source, it is unknown whether all or some of the content in the reference is unacceptable. Industry requires predictability for what portions of the reference (e.g., pharmacopeia or paradigm specific texts) are acceptable for the evidentiary support of the different types of health claim. This amendment will enable timely, efficient clarification for applicants about what is meant in the Information Request Notice. This is not a recommendation to change the Standards of Evidence guidance document.

Response to Recommendation 4: Agree

The NHPD always endeavours to be as clear and informative as possible through information requests notices (IRNs). Once a product has been fully assessed, if an IRN is issued, it lists specifically what is deficient about the evidence as it relates to the application and where possible potential solutions are offered. In order to aid applicants, educational workshops have been offered and will continue to be offered to allow a "hands-on" learning opportunity for NHP licence applicants to gain familiarity with, and increase their knowledge of, the electronic forms, tools and checklists available to prepare and submit a non-traditional NHP licence application to Health Canada. Further, the NHPD strives to have guidance documents up to date and provides ongoing training for staff in order to improve the clarity and consistency of communications regarding deficiencies.

Recommendation 5

The evidence levels (I to IV) in Table 2 (strength of evidence grading table) in the Guidance Document should be reviewed and clarified to enhance guidance for and consensus between industry and reviewers (when and how the various levels are used). Other recommendations in this report provide further specificity to this recommendation.

Recommended by: All PAC members

Rationale/Discussion: A full review of the Standards of Evidence levels and fuller clarification/definition to clarify and define the levels for applicants. There is a variation between the understanding of applicants regarding what falls into the guideline and what is applied by reviewers. This recommendation is linked to recommendations 4 & 6.

Response to Recommendation 5: Agree

The NHPD is committed to a full review of the Standards of Evidence requirements for different levels of claims submitted. This determination will include a review and clarification of the decision tree submitted by PAC members and the outcome of this review will be reflected within the NHPD guidance documents.

Recommendation 6

Evidence of previous market experience can be considered evidence for safe use in humans at a given dose if the product was consumed within an identified minimum number of years and/or minimum number of units sold and provided additional evidence supports the safe use in the market place (i.e., evidence of a low AR rate). The NHPD should undertake further investigation including seeking expert opinion from epidemiologists, to identify the required minimum number of units sold and minimum number of years on the market, with consideration given to AR reporting sources (e.g., country collecting), to be accepted as supporting evidence. The Guidance Document should be amended to clearly identify the requirements (parameters, specificity) related to using previous market experience as evidence. This guidance should be accompanied/supported by a form including the questions applicants need to answer when submitting this type of supporting evidence (e.g., number of years on market, source country of adverse event report...).

Noted regarding use of AR reports that adverse event reporting is poor in most countries and it would therefore be important to identify countries with recognized quality reporting, e.g., that collect comprehensive reports from industry, consumers and health care professionals. In addition, health care professionals should receive reports.

Recommended by: All PAC members

Rationale/Discussion: Guidance (predictive value) on the type of evidence required for the level of health claim is needed for industry (product licence applicants), e.g., how much and what kind of evidence is needed for non-traditional products. There is a need to clarify for applicants the conditions under which market experience is accepted as supporting evidence, this includes specifying aspects such as the minimum number of years the product has been on the market, the number of units sold and adverse event reports. There is a need to specify:

  • the international jurisdictions recognized by Health Canada as reliable sources of evidence for history of safe use - which meet requirements for (identified) minimum numbers of years on the market and reporting of ARs (some countries do not track adverse events)
  • minimum number of years and units sold according to the country where the product is manufactured, in consideration of the varying level of product safety in different jurisdictions.
  • minimum number of years of use by health care professionals (e.g., 5 to 10 years of use without adverse event) in consideration that long term use of a product by a health care professional occurs only where the product is considered to be without risk to the patient.

Response to Recommendation 6: Agree

The NHPD accepts the need to provide guidance on when and how international market experience can be considered as evidence. Please note that the NHPD has adopted certain tools that reflect this concept in the development of pre-cleared information (e.g. International documents where market experience has been used in the development thereof.) The NHPD will explore the feasibility of hiring a contractor(s) with the appropriate experience to examine this issue more thoroughly.

Recommendation 7

The NHPD should formalize the mechanism whereby information on review decisions (e.g., review report) is accessible to applicants, related to their applications, in order to facilitate feedback as appropriate. This is not related to refusals for which there is an appeal process in place (Reconsideration Process).

Recommended by: All PAC members

Rationale/Discussion: This will lead to improved quality of applications.

Response to Recommendation 7: Agree

Instructions on access to reports, including the Safety and Efficacy Assessment Report, have been included in the Application Management Policy.

Recommendation 8

There should be industry-consulted performance standards in place. The following performance targets were suggested: 180 days for non-traditional, non-compendial applications, 60-120 days for amendments (single and multi ingredient products; depending on the nature of the amendments), and 60 days for compendial applications. The implementation date of performance standards for the NHPD must be made public.

Recommended by: All PAC members

Rationale/Discussion: The idea of random assessments raises liability issues for the NHPD, and to avoid such issues assessments should be focused on streamlining the process within a fixed amount of time.

Response to Recommendation 8: Agree

The NHPD is committed to establishing performance standards. The Application Management Policy, a draft of which was presented to the NHP-PAC at the March 22-23, 2010 meeting, has been aligned with the proposed Natural Health Products (Unprocessed Product Licence Applications) Regulations.

Recommendation 9

The NHPD should accept animal evidence to support safety and efficacy where the animal model used is validated as an appropriate representation for humans, where there is also a long evidence of human use and/or market history. Animal evidence should not be accepted as the sole evidence supporting safety and efficacy of a natural health product. It should be clarified in Table 2 of the Guidance Document when/under what conditions animal studies can be used as evidence. The term 'long' needs to be defined.

Recommended by: All PAC members

Rationale/Discussion: Recognizes validated models and, where this validation does not exist, recognizes that animal models may not appropriately translate to humans, and that the bioactive substance being tested may behave differently. See Source Document 42 - description of physiologically based kinetic modeling approach used to "amplify" information from animal data in ways that render these outputs meaningful in the human context.

Response to Recommendation 9: Agree

The NHPD does not currently allow the use of animal evidence as the sole basis for supporting safety and efficacy of an NHP. The NHPD agrees that validated models can be considered and is examining the data available in this regard.

Recommendation 10

Cautionary statements, supported only by theoretical information, are not required to be used.

Recommended by: All PAC members

Rationale/Discussion: There needs to be evidence that an actual risk is likely to occur if there is to be a fair representation of the benefits and risks of a product. Otherwise needlessly warning consumers will reduce the benefit available to them by unnecessarily alarming them; thereby, creating an impression that they should avoid using the product.

Response to Recommendation 10: Agree

The NHPD is generally in agreement with this recommendation, and has always ensured that caution and contraindication statements are based on real risks and a complete review of the safety evidence provided when appropriate. However, the NHPD reserves the right to err on the side of caution when appropriate due to potential risks to consumers balanced with the health benefit(s).

Recommendation 11

Observational data should continue to be permitted as Level III evidence in Table 2 (strength of the evidence grading system) in the Guidance Document to support safety, provided the study is well designed (i.e., correlation studies, cohort studies, and case-control studies).

Recommended by: All PAC members

Rationale/Discussion: Observational data doesn't test hypotheses and are therefore not specific and relatively weak sources of data as the outcome of these studies could be due to a number of other factors.

Response to Recommendation 11: Agree

The NHPD currently accepts observational data provided that the study is well designed and relevant to the product. As part of the overall evaluation of Standards of Evidence as per Recommendation 5, NHPD will provide further guidance on how observational data should be used in the substantiation of claims, and what additional information would be required to support the safety of ingredients.

Recommendation 12

Qualitative studies should be considered as Level III evidence for efficacy where they are well-designed, validated surveys (e.g., correlation, cohort or case-control studies). The Guidance Document should be amended to clarify this.

Recommended by: All PAC members

Rationale/Discussion: Health Canada has stated it is open to preliminary meetings with sponsors to review their study methodology to determine whether or not it is sufficient. Cresswell (1994) defines qualitative study as an inquiry process to understand a problem using a complex holistic view/picture based on words, reporting of information, and conducted in a natural setting (e.g. anthropology, sociology). Therefore it is really inquiry, theory testing, data collection, and statistical analysis to determine if the theory is correct. As such correlation, cohort, case-controlled, analysis of use patterns and/or treatment patterns, analysis of expert opinion can be included as qualitative studies. From another source, valid qualitative studies do not require statistical analysis (Strauss and Corbin 1990). They accept the dynamic and complex nature of the human social experience and seek to understand it. One medical source says it is used extensively in primary care and patient care and includes detailed case studies.

Response to Recommendation 12: Agree

The NHPD is working towards a better understanding of when qualitative studies can be used, including defining the type of evidence required to support a health claim. The Guidance Document will be updated to reflect the decision taken.

Recommendation 13

As with clinical trials designed for risk reduction claims of Schedule A diseases, the Guidance Document should be amended to allow surrogate markers for clinical trials for supporting efficacy, provided data justifying the validity of the surrogate marker is provided.

Recommended by: All PAC members

Rationale/Discussion: Surrogate markers are discussed in section 4.3 of the HPFB draft guidance document for Schedule A and Section 3 to the Food and Drugs Act, which states:

"Risk reduction claims that are based on evidence generated by randomized, controlled, clinical trials with clinical outcomes that can be expressed either as a decreased incidence of the disease or a reduction of a factor, or a surrogate thereof, of the many that contribute to the development of a disease. Surrogate endpoints are risk biomarkers that can be used to predict disease risk provided that the relationship between the biomarker and the disease has been conclusively established. Substantiation of risk reduction claims involves the same scientific rigour as that applied to prevention claims and is based on the same types of study design and strength of evidence. The acceptability of utilizing a biomarker in lieu of clinical measurements of the incidence of disease or other clinical endpoints should be discussed with the appropriate Directorate prior to the initiation of studies involving the use surrogate markers. Data justifying the validity of the surrogate marker must be provided at that time."

Response to Recommendation 13: Agree

The draft Schedule A Guidance Document currently allows for the use of validated surrogate markers and endpoints when supporting claims. The NHPD has taken part in the development and revision of this guidance document and therefore is aware of, and will accept, risk reduction claim substantiation by the method indicated in this document, for claims related and unrelated to Schedule A diseases. We expect the final version of this document to be published by the end of the 2010.

Recommendation 14

Level IV studies are, generally speaking, secondary sources (with the exception of Expert Opinion Reports which are more primary) in that they do not put forward original (i.e., primary) data. The NHPD must embrace secondary data that is reputable (especially Pre-Cleared References) that may not always require validation of the primary data directly from the applicant. The NHPD should develop a short list of reputable journals which can be used as Pre-Cleared Information, and where journal data is not contradictory and the claim type and level is appropriate (e.g., not a treatment claim), accept two independent journal sources with the same conclusion (but not using the same referenced primary data) as supporting evidence for efficacy of a product. Information Request Notices should clearly state the reason(s) a journal reference was not accepted - see Recommendation #4. The applicant may be requested to provide the primary data to the NHPD, where the secondary data is not accepted.

Recommended by: All PAC members

Rationale/Discussion: At present, the NHPD accepts Level IV evidence if it references/discusses primary sources - and if the secondary sources do not summarize those primary sources in heavy detail, the NHPD will ask for the primary studies in turn. Scientific articles are often costly to purchase, or they may not be available in English or French (yet the review article discusses their details in English or French), and we must find ways of trusting the data. This especially holds true where the risk of failed efficacy is low. The reference to secondary sources generally refers to review articles rather than primary data published in a credible peer-reviewed journal. In order to develop a short list of acceptable secondary sources two criteria should be used. First, the peer review process should have the confidence of the regulator. Second, the review article should accurately represent the primary research within the context of the claim in the applicant's submission.

Response to Recommendation 14: Agree

The NHPD is continually seeking new sources of pre-cleared information, and when appropriate will consider references and the rationale for their inclusion as PCI. In the meantime, the NHPD is focusing on developing PCI for as many medicinal ingredients as possible in order to facilitate an efficient assessment process.

Recommendation 15

Expert Opinion Reports may only be considered as Level IV evidence supporting the efficacy of a natural health product if the report meets all of the criteria listed in section 3.5 of the Guidance Document.

In lieu of an Expert Opinion Report developed by three authors, the Guidance Document should be amended to accept a meta-analysis of a significant number of expert opinion reports compiled by single authors. The meta-analysis must provide credentials of the experts analyzed in order to ensure the credibility of the meta-analysis.

Such reports could be used to provide validation of an animal model, evidence for dosing issues or for demonstrating rationale in cross-paradigm combinations.

Recommended by: All PAC members

Rationale/Discussion: Health Canada has stated they are open to preliminary meetings with sponsors to review their study methodology to determine whether or not it is sufficient. Three independent sources (authors), representing agreement between three experts provides a reasonable amount of supporting evidence. Range of dose should be considered.

Response to Recommendation 15: Agree

As part of the overall review for standards of evidence, the NHPD will revise its policy in reference to the use of expert opinion reports.

Recommendation 16

Safety must be demonstrated (crude equivalent if extract) based on dose ranges from traditional medicine, clinical trials or previous marketing experience, idea of excipient being the same. See recommendation #10. Where previous marketing history is the only human data, animal toxicity studies must be provided as well. A crude equivalent extract can be physically altered such as drying, grinding or extracting using a traditional excipient but not chemically altered. From crude plant material a wide spectrum extract is produced. This wide spectrum extract can be a liquid or dried to a relatively low concentration (usually 5:1 or lower). Any higher concentration that has been fractionated or altered with a different excipient is not considered an equivalent.

Recommended by: All PAC members

Rationale/Discussion: Where non-standardized extracts are involved, safety need only be supported on the basis of calculating crude equivalents (i.e., based on extract/tincture ratios), and the specific preparation method would not have to match that of a reference for such non-standardized extracts, provided the crude equivalent is supported. NHPD monographs are typically written in this way, in that all non-standardized extracts are generally considered equivalent to one another (so long as they are comparable based on crude equivalent).

Response to Recommendation 16: Agree

The NHPD received further clarification on this recommendation during the March 22-23, 2010 meeting and based on this feedback, the NHPD will prepare text for the guidance document on comparability of extracts and whole herbs, which initially will be communicated to stakeholders as an interim communiqué.

The NHPD will examine and clarify the definitions and terminology for extracts. Ideally this terminology should be harmonized internationally; however complete harmonization will necessarily be a long term process. This will be done in conjunction with recommendation 23 of the Product Testing Working Group.

Further elaboration of the basic information on extracts is required in order to provide substantial guidance and related training for stakeholders about characterisation of whole herbs and extracts. Where possible, this will be linked to recommendation 3 of the Product Testing Working Group to develop specific guidance on identity testing in consultation with industry and academic experts.

Recommendation 17

For multi-ingredient non-traditional products, where the individual ingredients attest to NHPD Monographs, the Compendium of Monographs guidance should be amended to allow monograph combination products to be evaluated under the 60-day disposition, provided no safety concern exists for the combination and a rationale supports the logical combination of the ingredients (i.e., they all support the same organ system, all treat the same symptom or prevent the same illness etc).

Recommended by: All PAC members

Rationale/Discussion: The review process was also discussed in terms of possible flexibility reflecting the industry's need to balance market access with the ability to generate quality data supporting efficacy over time.

Response to Recommendation 17: Agree

The NHPD initiated a pilot project to determine the feasibility of evaluating these products with a 60 day performance target. Where there are no safety concerns for the combination and a rationale supports the logical combination of ingredients, the 60 day performance target is feasible.

However, in practice, the pilot project revealed that many of the applications do not meet these requirements and are significantly more complex and hence time-consuming than files in the compendial stream. For example, an application containing eight medicinal ingredients indicated for "sleep aid" with each ingredient supported by a monograph for "sleep aid", would still require the evaluation of the safety and efficacy effects of the combination due to concerns over adverse additive and/or synergistic effects.

As a result the 60 day performance target cannot be established for all these products at this time. The NHPD will work to develop a list of appropriate/non-appropriate combinations.

Recommendation 18

For the combination of ingredients that are individually supported in terms of safety and efficacy by Level V traditional evidence from the same paradigm, or from both traditional & non-traditional evidence sources, the Guidance Document should be amended to permit their novel combination, in absence of any known safety concern, under the non-traditional review stream if accompanied by a rationale for their combination and at least one additional piece of evidence (Level I-IV) which adequately supports safety and efficacy of that combination in humans. An example of the claim wording would be: "these ingredients are traditionally used to promote sleep".

Recommended by: All PAC members

Rationale/Discussion: Novel combination of (traditional-use) ingredients make a product novel, thus it would be a non-traditional application and adequate evidence should be supplied to support its safety and efficacy in humans as well as a rationale for the combination of the ingredients. Section 2.2.1 of the Guidance Document states that "If traditional and scientific evidence are available to support a proposed claim, the applicant may choose whether to use the wording "traditionally used...". If a health claim is solely supported by scientific evidence, it must not include the words "traditionally used..." If traditional and scientific evidence are available to support a proposed claim, then both the scientific and traditional evidence must be independently sufficient to support the safety and efficacy of the product. Traditional evidence cannot be used to "top up" a deficiency in scientific evidence. The claim should maintain the language to communicate to consumers that the evidence is of traditional nature so as to not confuse traditional and non-traditional evidentiary support, i.e., "the ingredients are traditionally used for..." It is important for consumers to know the source of the evidence used. This change would allow claims (labels) that would not otherwise be permitted (if not permitted to use evidence from both sources).

Response to Recommendation 18: Agree in principle

The NHPD currently allows applicants in the non-traditional stream with non-traditional claim(s) to enhance their application with the addition of an appropriate traditional claim(s). Under certain circumstances, the combination of ingredients that are individually supported for safety and efficacy by Level V evidence from the same paradigm is acceptable to the NHPD, when there are no safety concerns and the combination is rationalized with sufficient evidence to support safety and efficacy of that combination in humans. It will be important that the claim(s) respect the traditional health paradigms of the respective medicinal ingredients.

Recommendation 19

For the combination of ingredients that are individually supported in terms of safety and efficacy by Level V traditional evidence from different traditional paradigms, the Guidance Document should be amended to permit their novel combination, in absence of any known safety concern, under the non-traditional review stream if accompanied by a rationale for their combination and at least one additional piece of evidence (Level I-IV) which adequately supports safety and efficacy of that combination in humans, e.g, licorice - where the two evidence sources for dose, can be from two different paradigms for dose, and another paradigm can be used for efficacy. An example of the claim wording would be: "these ingredients are traditionally used to promote sleep." The Guidance Document should be amended to reflect this.

Recommended by: All PAC members

Rationale/Discussion: Novel combination of traditional-use ingredients make a product novel, thus it would be a non-traditional application and adequate evidence should be supplied to support its safety and efficacy in humans as well as a rationale for the combination of the ingredients. Section 2.2.1 of the Guidance Document states that "If traditional and scientific evidence are available to support a proposed claim, the applicant may choose whether to use the wording "traditionally used...". If a health claim is solely supported by scientific evidence, it must not include the words "traditionally used..." If traditional and scientific evidence are available to support a proposed claim, then both the scientific and traditional evidence must be independently sufficient to support the safety and efficacy of the product. Traditional evidence cannot be used to "top up" a deficiency in scientific evidence. The claim should maintain the language to communicate to consumers that the evidence is of traditional nature so as not to confuse traditional and non-traditional evidentiary support, i.e., "the ingredients are traditionally used for..." It is important for consumers to know the source of the evidence used. This change would allow claims (labels) that would not otherwise be permitted (if not permitted to use evidence from both sources).

Response to Recommendation 19: Agree in principal

In principal, it may be acceptable to make a single claim for a combination of ingredients that are supported by traditional evidence from different paradigms, if accompanied, as per the recommendation, by a rationale for their combination and at least one additional piece of evidence which adequately supports safety and efficacy of that combination in humans. It will be important that the claim(s) respect the traditional health paradigms of the respective medicinal ingredients given that each paradigm can be rather specific in its understanding and approach to dealing with a noted health condition.

Recommendation 20

Products supported by "Pre-Cleared Information", in the NHPD risk-based assessment process, should not require a full evaluation of evidence, only a screening of the paperwork. Validation of these products should be undertaken through random inspections.

Recommended by: All PAC members

Rationale/Discussion: To speed up application process.

Response to Recommendation 20: Agree in principle

The NHPD defines pre-cleared information as any form of information supporting the terminology, safety, efficacy or quality of a medicinal ingredient, non-medicinal ingredient or natural health product that NHPD has reviewed and determined to be acceptable and includes NHPD monographs and Abbreviated Labelling Standards. Currently, an application that is supported by pre-cleared information receives an expedited review. The NHPD continues to seek process improvements regarding the use of pre-cleared information and expects that as the use of the electronic application process increases, more efficiencies will be realized.

It should be noted that the NHPD does not re-evaluate pre-cleared evidence, but rather evaluates whether the evidence matches the claim. Experience has shown that random inspections are not feasible at this time.

Recommendation 21

The Guidance Document should be revised to include a decision tree that focuses on application type. The NHPD should review the draft decision tree and advise the Committee of any further required input. It is the expectation of the Committee that there will be further input required from it.

Recommended by: All PAC members

Rationale/Discussion: The focus should move away from describing the conditions (level of evidence required for type of claim) towards a focus on describing application types (licensing requirements and stream).

Response to Recommendation 21: Agree

The NHPD commits to a full review of the Standards of Evidence required for particular claims and will evaluate the decision tree provided by PAC as part of this review.

Recommendation 22

Health Canada should only approve health claims on products when the data supports the proposed dose or dosing range.

Recommended by: All PAC members

Rationale/Discussion: The current standards of evidence do not restrict product sponsors from being able to market products with low doses, provided they have some support for their use for a health outcome at that low dose. This standard already applies to traditional products.

Response to Recommendation 22: Agree

The NHPD currently accepts health claims on products where the data supports the proposed dose or dosing range. Please see response to Recommendation 25 for further clarity regarding acceptable dose and dosing range.

Recommendation 23

The NHPD should continue to review existing Aromatherapy/essential oil textbooks and seek advice from experts in the field to determine the allowable claims for topical use and ingested products, which are supported under the current standards of evidence.

Recommended by: All PAC members

Rationale/Discussion: Advice needed to help fill gap for essential oils related to lack of data supporting the safety and dosage.

Response to Recommendation 23: Agree

NHPD is currently working towards developing options for appropriate licensing requirements for products containing essential oils and claims related to aromatherapy in conjunction with the overall review regarding appropriate standards of evidence.

Options for developing appropriate pre-cleared information for topical and inhalation applications are being examined, while also identifying safety concerns that can be associated with ingestion and rectal delivery of aromatherapy products.

Recommendation 24

The NHPD should continue to pursue development of further sources of Pre-Cleared Information and therefore add more products and/or ingredients to the Class I licence application review:

  • Validate List of References (Appendix A) provided by the Task Group through consultation with experts including health care professionals, and adopt as Pre-Cleared Information those appropriately validated references.
  • Revise Guidance Document to include the Pre-Cleared Information references with identification of the specific aspects the reference supports (i.e., evidence for safety, efficacy and/or non-medicinal ingredient of the product) under the current standards of evidence.
  • Consult with the natural health products industry and health care practitioners to nominate foreign monographs to be reviewed and possibly adopted into the Compendium of Monographs.

Recommended by: All PAC members

Rationale/Discussion: Task Group on References: S. O'Reilly (lead), P. Saunders, M. Jutras, S. Aberdour, (B. Wagner, A. Kingsley, observers). Pre-Cleared Information sources provide predictability and establish awareness of acceptable reference sources for stakeholders, in particular product licence applicants. The proposed list of references in Appendix A represents references (e.g., pharmacopeia and paradigm specific texts) identified in consultation with health care professionals as references that are commonly used by health care professionals in Canada. To address the need to provide additional data to support the efficacy, it is suggested that the industry collaborate with credible researchers internally, government agencies, and through research-based associations.

Response to Recommendation 24: Agree

NHPD will continue to develop pre-cleared information as quickly as possible. Collaboration will be used where feasible to develop and validate references and sources.

Recommendation 25

Where two references for the same indication support two different safe and effective doses, the product should be permitted with a dose that falls within that dosage range. The Guidance Document should be amended to clarify this.

Recommended by: For - 11; Abstain - 2

Rationale/Discussion: The Regulations specify there must be a dosage. Dose is linked to the discussion on risk: risk-based approach and use of Pre-Cleared Information, classes of licences (risk categories). Dosage range to meet gaps.

Response to Recommendation 25: Agree

Where two references have conditions of use or study end points that are the same and review of the evidence does not raise safety and/or efficacy concerns, the dose can fall between the range or a dosage range can be approved.

Recommendation 26

Health claims continue to be mandatory with at least one claim per product and a minimum of one independent reference required to support a claim. The strength of the claim is directly proportional to the strength and credibility of the evidence provided.

Recommended by: All PAC members

Rationale/Discussion: Matches claim to the evidence (the claim determines the evidence required); supports innovation. The preponderance of evidence supports the claim.

Response to Recommendation 26: Agree

This recommendation is consistent with the Natural Health Products Regulations, which require a recommended use or purpose as defined in the Regulations.

Recommendation 27

The Guidance Document should be amended to clarify that where a product licence application lacks the evidence to support the proposed health claim but (i) the submitted evidence does support another health claim with minor adjustments or (ii) a new monograph in the Compendium of Monographs or an Abbreviated Labelling Standard is available, the NHPD should contact the applicant to provide advice. A process should be implemented to provide an opportunity for applicants to clarify to the NHPD the intent of the evidence used to support the claim (submission meeting).

Recommended by: All (Note - absent: 2)

Rationale/Discussion: Speeds up application process.

Response to Recommendation 27: Agree

The NHPD has a process for requesting pre-submission meetings and applicants can communicate with the NHPD during the assessment process to clarify the intent of the evidence used to support the claim. If applicable, the NHPD will provide claim modifications that are supported by pre-cleared information. However, the onus is on the applicant to keep up to date on published Monographs/AbLS documents and to consider amending/revising claim(s) in response to an IRN based on such documents, provided that all elements of this PCI are met and adhered to.

Recommendation 28

Appendix 5A of the Guidance Document should be amended to explain that the template for additive combinations may not be appropriate for some combinations of natural ingredients. The NHPD should seek advice from experts in the field in order to determine if a logic model template for the additive effects of herbs with other ingredients could be developed. The NHPD should refer to health care professional models of blends.

Recommended by: All (Note - absent: 2)

Rationale/Discussion: The additive combination template does work when for herbal products; it is a different challenge than when the combination contains vitamins or minerals or other type of ingredients. There should be a distinction made between the two.

Response to Recommendation 28: Agree

The NHPD is examining how best to address combination products and evaluating whether the additive combination template should be updated or a new approach developed.

Recommendation 29

The NHPD should accept all fungal enzyme product applications regardless of source on the understanding that the NHPD is currently compiling material on this topic, which will be brought back to the Committee for further discussion

Recommended by: All PAC members

Rationale/Discussion: Safe history of use of fungal enzymes on the market. Applications for the licensing of fungal enzymes currently fall into three categories:

  • applications that include adequate evidence supporting a claim and a safe dosing range;
  • applications for licenses which are transferred to Natural Product Number (NPN) status from the Drug Identification Number (DIN) registration system; and,
  • applications that do not have adequate evidence supporting a claim or a safe dosing range and did not have a previous DIN license.

For the first category, a license can be granted under the full application of the regulations. For the second category, these products have been granted a market continuance under a transitional provision that recognizes that there had been a DIN granted but the pre-existing conditions of DIN licensure may or may not have met the standards of evidence under the natural health products regulatory system. The policy is deemed transitional and allows such products to continue to be sold whether or not the original evidence used to make the licensing decision would meet current standards.

Such a system gives rise to two sub-classes. The first is a transitional DIN that has adequate evidence to meet the current standards and the second is where the evidence is insufficient to meet the current standards. The former can be granted a license under the full application of the regulations. The latter sub-class gives rise to a concern that such products do not meet the standards but should be given the opportunity to update their evidence, or to revise their claim so that a license can be granted under the full application of the regulations.

For the third category, a license cannot be granted under the full application of the regulations.

Recommendation for Transitional provisions

Where a product is granted transitional DIN registration and there is insufficient available evidence to confirm its licensure under the full application of the regulations, NHPD should issue a notice of consultation to conduct a review of the ingredients in question. During this consultation ingredients under review may continue with their assigned license subject to the final determination of the review.

Exception for equitable access

During the class review of evidence, other products may apply for licenses for formulations equivalent to an already licensed product under the transitional provisions. If deemed to be equivalent then a transitional license may be granted and the product may continue with their assigned license subject to the final determination of the review.

Note: If a product formulation is not equivalent to that outlined under the exception conditions it would, by definition, be in the "third category" and a license cannot be granted under the full application of the regulations.

Response to Recommendation 29:

An update on Fungal Enzymes was presented by the NHPD at the NHP-PAC meeting on June 14, 2010. NHPD has developed Abbreviated Labelling Standards for several enzymes, however there are still gaps in the evidence. NHPD will continue to work with associations and applicants to complete these documents. For enzymes where there is no evidence for efficacy, files will be refused. NHPD will communicate with stakeholders about the evidence deficiencies.

Recommendation 30

Recommendation regarding medicinal ingredients and non-medicinal ingredients in Non-Traditional natural health products. For medicinal ingredients, the claim is based on a therapeutically dosed ingredient or ingredients according to an additive table. There may be other medicinal ingredients that are a part of the formula. They must be safe, as demonstrated by at least one reference and in consideration of the totality of evidence, and there must be evidence to support the rationale for their inclusion as medicinal ingredients in the formula. Medicinal ingredients should appear on the label quantitatively.

If the formula cannot satisfy the conditions above, providing the ingredients are safe, the group felt that one of two approaches could be taken:

  1. list those ingredients as non-medicinal ingredients without requiring further evaluation.
  2. allow those ingredients to be used as non-medicinal ingredients only if the ingredient meets NHPD current non-medicinal ingredient definition for their non-medicinal use.

Guidance documents should be amended to provide clarity for both applicants and reviewers.

Recommended by: All PAC members

Rationale/Discussion: It facilitates a more informed choice and prevents misleading claims. There are many ingredients which would not meet a dose requirement -- on their own or via an additive effect -- but which the manufacturer still has sound reason to believe is not an innocuous/non-medicinal ingredient, albeit cannot demonstrate this from a dosing perspective. This is of paramount importance to preserving innovation -- if companies cannot experiment with safe ingredients for creating novel formulations, we lose innovation. Even as such, it is still expected that at least one medicinal ingredient supports at least one health claim, as the bare minimum. Because the NHPD currently licences multi-ingredient products not requiring every medicinal ingredient to have a supported claim (albeit a rationale is required to justify its presence still), labelling such "rationalized" ingredients as medicinal ingredients might be misleading to consumers. Consumers must know which ingredients form the basis for the product claims, in order to make truly informed decisions. Permitting medicinal ingredients at non medicinal levels without an adequate rationale or supporting evidence runs the risk of misleading the consumer into believing that the ingredients are providing significant benefit, when there is a reasonable chance that they are having little or no real effect. For example, ingredients known to have a therapeutic dose range in the 100's of milligrams, are unlikely to be providing significant effect when used in doses such as 5 or 25 mg, even if they are combined with ingredients with which they may have a synergistic effect. Although the philosophy of "synergy" in complementary and alternative medicine and herbal medicine is an important one, there must be reasonable limits placed on how low a dose of an ingredient can be allowed under this philosophy. Synergy alone cannot be used to justify the use of medicinal ingredients at non-medicinal ingredient doses, particularly when there is very large gap between established therapeutic dose ranges and those being proposed in a combination natural health product.

NHPD Response: Agree in principle

Over the years, our experience has shown that products contain ingredients that are sub-therapeutic or for which the minimum efficacious level is disputed. Ingredients are added based on animal studies that show promise, or early clinical trials that suggest benefits but are insufficient to support claims by themselves. When NHPs were regulated under the Food and Drug Regulations, there was no declaration of non-medicinal ingredients (NMIs), therefore many ingredients with the potential for pharmacological activity were not declared as medicinal ingredients. The Natural Health Products Regulations however, require these ingredients to be listed as medicinal ingredients unless there is a known non-medicinal use for the ingredient. Labeling these ingredients as MIs, with the quantities on the label, provides consumers and health care practitioners with the ability to make informed choices and evaluate potential impacts of the ingredients. This can be especially important given that certain ingredients are consumed in multiple products with potentially deleterious additive affects (ex. gingko).

Given this context, the NHPD is proposing to revise its guidance documents in order to better reflect current practices and the standards of evidence required to substantiate the inclusion of medicinal ingredients in multiple ingredient products.

In addition, the NHPD is proposing that the definition of non-medicinal ingredients be expanded in order to encompass a wider range of NMI purposes. As a result of this proposal, over time, a greater number of ingredients will be available for listing as an NMI. The applicant will be responsible for providing the NHPD with sufficient information to warrant listing an ingredient with pharmacological effects as an NMI, including establishing an upper limit at which an ingredient would no longer be acceptable as an NMI for the particular purpose.

As part of this expansion for NMI purposes, the NHPD will require applicants to provide the NMI quantities as part of the assessment. Further, the NHPD will retain the right to restrict particular ingredients at sub-therapeutic quantities as MIs or NMIs.

Recommendation 31

For multi-ingredient non-traditional products, where the individual ingredients may have a synergistic or additive effect, the Guidance Document should be amended to permit their combination in a formulation that is supported in terms of safety and efficacy by evidence Level I-IV. Health care professional models for blends should be used by the NHPD for evidence on combinations/blends.

Recommended by: For - 11; Abstain - 1

Rationale/Discussion: This Recommendation is linked to Recommendation #28. To be useful and informative for applicants, the additive table needs to be revised to clarify the requirements (reasons) for additives. This addresses one of the most difficult aspects/concepts for applications. Neither applicants nor reviewers know what is expected (there is no tradition for the combination, but there is for the components). It is possible to capture the tradition of the component and thereby rationale for the blend, but there is currently no vehicle to do this. As long as the formulation is supported by evidence: a third category. There is a history of use for blends available through health care professional models which can provide evidence for combinations, including theory behind the blend. Key to innovation.

Response to Recommendation 31: Agree

See response for recommendation 28.

Recommendation 32

Disclaimers on products not meeting the standard of evidence required to support a health claim should not be granted market access. It is up to the discretion of the NHPD reviewers, acting as agents of the Minister of Health, to determine if qualified wording is necessary, given the evidence provided, that the product is likely to produce the intended effect, however qualified wording should be avoided in general as the concept of probability is inherent within the product review process.

Recommended by: For - 7; Against - 4; Abstain - 1

Rationale/Discussion: Disclaimers (clarify term) place an unfair burden on the consumers to judge the health merit of the product for sale.

Response to Recommendation 32: Agree

The NHPD does not currently allow disclaimers on products and the use of qualified wording will be evaluated on a case-by-case basis. The NHPD will continue to focus on generating pre-cleared information, which will indicate when qualified wording is necessary and acceptable.

Recommendation 33

Qualified wording on products meeting the standard of evidence required to support a health claim should be granted market access. It is up to the discretion of the NHPD reviewers to determine if qualified wording is necessary, given the evidence provided, that the product is likely to produce the intended effect. An "appeal" process should be implemented to provide an opportunity for applicant to clarify the intent of the qualifier used.

Recommended by: For - 5; Against - 6; Abstain - 1

Rationale/Discussion: As long as a health claim is clear and there is supporting evidence (safe, effective), the claim should be permitted. This supports innovation and life cycle using potentially interim claims with changes made once more robust data is available. Qualified wording can help to inform the consumer.

Response to Recommendation 33: Agree

See response for recommendation 32.

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