Natural Health Products Research Program (NHPRP) - Bridging the Regulatory Gap:
Funding priorities in NHP safety, quality and efficacy

---

Table of Contents

Introduction
Rationale
NHPRP Objectives
Scope of the Current Solicitation
Priorities for Funding
Eligibility Criteria
Who is Eligible to Apply?
What are the Eligible Costs?
How Much Funding can a Proposal Receive?
How Long can the Project Last?
How will Proposals be Reviewed?
Audit Process (if proposal is funded)
Intellectual Property
Proposal Requirements
Administrative and Reporting Requirements (if proposal is funded)
Application and Submission Details
Bridging the Regulatory Gap: Funding priorities in NHP safety, quality and efficacy - Application Form (PDF Version)

---

Request for Proposals

from the Natural Health Products Directorate

Health Products and Food Branch, Health Canada

April 01, 2005

Introduction:

The Natural Health Products Directorate (NHPD) is the regulatory authority for natural health products (NHPs) sold in Canada. The role of the NHPD is to ensure that Canadians have ready access to NHPs that are safe, effective and of high quality while respecting freedom of choice and philosophical and cultural diversity.

Following a national consultation process, new Natural Health Product Regulations were published on June 18, 2003. These regulations, which place requirements on those who manufacture, package, label, import or distribute NHPs, are intended to regulate substances that are safe for over-the-counter use. NHPs include plant or plant materials such as herbal products, isolates extracted from plant materials, vitamins, minerals, amino acids, essential fatty acids and homeopathic products that are used to diagnose, treat and/or prevent disease, restore or correct function or maintain or promote health.

In addition to its role as product regulator, the NHPD is committed to supporting NHP research. In order to determine how best to fulfill its research mandate, the NHPD held a series of consultations with key stakeholder groups to determine research priorities. In June 2003, the NHPD launched the Natural Health Product Research Program (NHPRP) to address these priorities.

The NHPRP has been developed to reflect the diverse nature of the NHP research community. While the primary interest of the NHPRP is to support product based rather than practice based projects, proposals exploring complementary and alternative health care (CAHC) will be considered provided they demonstrate a significant focus on NHP research. For example, while chiropractic or acupuncture research in itself does not meet the NHPRP criteria for funding, research investigating the use of NHPs by chiropractors or acupuncturists is suitable for consideration.

Rationale:

The Contribution program for the NHPRP is an integral part of the research mandate of the NHPD.

Even though Canadians are increasingly utilising NHPs, the growing demand for health-care research means that initiatives in this subject area often do not get the attention they deserve. The scope of the NHPRP is to germinate research interest in NHP research and direct funding to research and related activities that:

• are relevant to the regulatory function of the NHPD;
• enable consumers to make informed choices about NHPs; and
• are sensitive to the needs of the communities and traditions that produce and utilize these products.

NHPRP Objectives:

The objective of the NHPRP is to contribute to improved knowledge of NHPs, including their safe and effective use, by supporting research in various forms, including biomedical, product quality, clinical, health services and population health, and by making information accessible to stakeholders and consumers.

To meet its objectives, the NHPRP will focus on and aim to achieve results in four key areas:

• Building research capacity;
• Supporting the conduct of research;
• Fostering collaboration, community infrastructure and partnership building; and
• Enhancing information retrieval and knowledge transfer.

Scope of the Current Solicitation:

Throughout the research consultations, stakeholders have identified that the NHPRP could play a key role by supporting projects in their early stages of development. As such, this RFP has been developed to target research projects at their inception and provide support via contribution funding. While not directly supporting the conduct of NHP research, this RFP seeks to facilitate the development of research projects.

The specific activities suitable to this type of funding should reflect the scope of this request for proposal (RFP). Activities considered suitable for funding include but are not limited to:

• Preparation of research proposals e.g. clinical trials, pre-clinical research;
• Preparation of business cases for research networks and societies;
• Literature reviews necessary to support larger research initiatives.

While the preparation of proposals to seek funding for clinical trials is eligible, funding for clinical trials is not eligible under this initiative and should be submitted through the Canadian Institutes of Health Research.

Scheduled conferences or symposia is not an eligible activity under this RFP, the NHPRP anticipates launching a separate RFP for this type of support within the next few weeks.

Priorities for Funding:

Access to NHPs is balanced with safety, quality and effectiveness. Much work remains to expand the evidence base that supports the safety and efficacy of NHPs and to improve the research-based knowledge of NHPs in general.

Proposals must address one or more of the specific topics identified under the following priority areas:

(1) Safety of NHPs

Evaluating the safety of NHPs can be challenging given that the full range of safety and toxicological data are not always available. The standards of evidence used by the NHPD accept a variety of types of evidence to support the safety of an NHP, including traditional references, adverse reaction reports, history of use, clinical data and toxicological data. One component of evaluating the safety of an NHP is the provision and assessment of information and data that supports the safety of the NHP when used in accordance with the recommended conditions of use. In addition, effective post-marketing surveillance plays an important role in the ongoing evaluation of NHP safety. The following topics have been identified as funding priorities in the regulation of NHP safety :

• Pharmacovigilance and safety monitoring initiatives that facilitate effective adverse reaction reporting by NHP users;
• Research into the long term/extended use of an NHP;
• Research involving drug interactions with NHPs;
• Effective information and knowledge management related to improving public access to NHP safety data;
• Research investigating the use of NHP's in pregnancy, childhood, among the elderly;
• Safety of NHPs used for weight loss and athletic performance.

(2) Quality of NHPs

The quality of NHPs is an important issue in consumer confidence and protection. Submission of evidence related to quality includes the submission of information on GMPs. GMPs identify requirements for premises and equipment, personnel, processes (sanitation, operations) and products. In addition, GMPs identify general quality specifications such as intolerance limits for contaminants, and more specific markers such as tests to identify species or variety of herbs or for levels of active or toxic constituents. The following topics have been identified as funding priorities in the regulation of NHP quality:

• Development/improvement of methods for assessing botanical identity, such as appropriate marker selection, validation of analytical methods, analytical competence and reference standards, development and validation of bioassays, and characterization of bioactive compounds;
• Determination of appropriate quality measure/methodology of formulation for traditional medicines;
• Initiatives that foster partnership/collaboration between stakeholders, possibly through the development of a cohesive quality research network to close quality research gaps;
• Research investigating the storage requirements of a plant, extract, tincture or other preparations that may require special conditions (e.g. humidity, temperature, protection from light);
• Development of appropriate methodologies to assess the quality of non-human animal products, including homeopathic products;
• Stability of vitamins and amino acids during the manufacturing process;
• Improvement of assays for constituents of known therapeutic activity or markers, for example, development of new methods for standardizing the potency of a plant/plant material (methods available now, e.g. HPLC/GC, may not be suitable for plants with very complex chemical profiles as interference is too high);
• Research investigating the possible effects of metals, contaminants, foreign materials, adulterants, microbial contamination, aflatoxins, mycotoxins, etc. in NHPs;
• Establishment of criteria for standardization of common name nomenclature for labeling purposes, e.g. Eleuthro/Siberian Ginseng;
• Exploration of levels and range of toxic elements (other than Pb, As, Hg, Cd) in NHPs;
• Examination of whether the identity/tolerance limits of select NHP medicinal ingredients listed on the label match the contents of the bottle and/or stability testing of NHPs within the label expiry date;
• Correlation of biochemical pathways with biomarkers in medicinal plants to evolve a systematic basis for the chemotaxonomy of medicinal plants;
• Studies on the growth potential of pathogenic bacteria on select biomarkers/active constituents;
• Development of a proactive safety system to identify and eliminate potential physical, chemical or microbiological hazards in NHPs via analysis of applicable hazards, identification of critical points in manufacture, and establishment of control point limits and monitoring protocols.

(3) Efficacy of NHPs

The NHP definition allows for a full range of health claims under the new NHP Regulations, including structure-function, risk reduction and therapeutic or treatment claims. A structure/function claim is related to the effect of an NHP on a human body structure or a physiological or mental function. A risk reduction claim type refers to reduction of a major risk factor for a chronic disease or abnormal physiological state. A treatment claim generally relates to the diagnosis, treatment or cure, mitigation or prevention of disease, disorder, abnormal physiological state or its symptoms. The amount and type of evidence required to make a claim is graduated, depending on the level of the health claim. Claims are assessed against evidence levels ranging from references to traditional uses to well-designed systematic reviews and meta-analyses of randomized control trials. The following topics have been identified as funding priorities in the regulation of NHP efficacy:

• Efficacy/bioavailability of an NHP delivered via various dosage forms or routes of administration, i.e. extended release, oral vs. buccal;
• Use of NHPs for "wellness" and health promotion;
• Evaluation of evidence from traditional healing models and systems, e.g. Traditional Chinese Medicine (TCM), Ayurvedic medicine, homeopathy;
• Establishing quantity unit conversions and activity for compounds that deliver the same medicinal ingredient but have different chemical structures, e.g. Vitamin E, Vitamin A, Beta Carotene;
• Use of NHPs in enhancing athletic performance and weight loss;
• Quantifying the bioavailability of compounds that deliver the same medicinal ingredient but have different sources, e.g. Glucosamine Sulfate, Glucosamine Sulfate 2KCl, Glucosamine Sulfate HCl etc.;
• Investigating bioactive constituents of aromatherapy products, establishing minimum dose and herb/herb synergies;
• Development of research methodologies of potential use in the evaluation of NHPs such as Nof1 within the context of the Canadian NHP Regulations.

Eligibility Criteria:

Proposals must contribute to the NHPRP's objectives, address one of this solicitation's funding priorities, fall within the type of activities suitable for funding and be multi-stakeholder in nature. For the purpose of this RFP, multi-stakeholder is defined as actively involving at least 2 of the following stakeholder groups:

• Conventional health care providers e.g. medical doctors, dentists, nurses, pharmacists;
• Members of the research community;
• Complementary and alternative health care providers e.g. naturopaths, homeopaths , herbalists or complementary medical doctors;
• NHP Industry;
• Community groups and Non-Government Organizations providing information or services to Canadians about NHPs;
• Provincial or Territorial governments.

Who is Eligible to Apply?

Organizations eligible to apply for "Bridging the Regulatory Gap: Funding priorities in NHP safety, quality and efficacy" include:

Voluntary Organizations: Canadian voluntary and not-for-profit organizations with a role or interest in NHP research;

Governments: Provincial and territorial governments and agencies;

Institutions: Not-for-profit educational, health, medical, social policy and research organizations, institutions, agencies; and

With respect to research, individual investigators including researchers, scholars, and health professionals, who propose to undertake health research at a Canadian university, affiliated institution or other recognized centre are eligible to apply for funding. This may include individuals in the following three categories:

Principal Applicant: The principal applicant has primary responsibility for the intellectual direction of the research and assumes administrative responsibility for the contribution. The principal applicant is a researcher who holds his/her major academic appointment, whether full- or part-time, at a Canadian university, affiliated institution or any not-for profit entity which is capable of administering fund in trust, and providing ethics review and meeting other regulatory requirements. The university or institution must have agreed to allow the investigator responsibility for directing research projects and supervising graduate students. While there may only be one principal applicant for each contribution proposal, there may be more than one co-applicant and/or associate.

Co-Applicant(s): The co-applicant is a researcher who holds his/her major academic appointment, whether full- or part-time, at a Canadian university, affiliated institution or any not-for profit entity which is capable of administering fund in trust, and providing ethics review and meeting other regulatory requirements. Co-applicants do not include trainees, research associates/assistants or foreign citizens.

Associate(s): An associate may include, in addition to the above, an individual(s) who makes a substantial intellectual contribution to the research project or application. Associates do not need to be affiliated with a Canadian university. Examples include graduate students, postdoctoral fellows, research associates/assistants and foreign colleagues.

For the purpose of this RFP, in the case of a not-for-profit entity, which is not a university or centre of higher learning, a researcher can be defined as including a full time employee of the organization with a responsibility for research.

The Principal Applicant is the person responsible for the intellectual direction of the proposed research. The Principal Applicant contributes his or her expertise and time to the project and does not receive a salary, stipend or honorarium from the NHPRP contribution. Only one person may be the Principal Applicant. Employees of Departments and Agencies of the Government of Canada and Federal Crown Corporations may not be principal applicants or receive any funding.

What are the Eligible Costs?

Funding will cover costs, in accordance with Treasury Board Guidelines, directly related to the activities of the proposed activity.

In general, eligible expenses include:

• Personnel and related costs directly associated with the initiatives;
• Reporting costs;
• Material and supplies;
• Travel and accommodation ( within TB Guidelines) for meetings;
• Hospitality ( within TB Guidelines);
• Communications costs;
• Research and development that improves the quality of information and data on NHPs; and
• Other costs that are time limited in support of the initiatives and consistent with the objectives of the research initiative.

The costs for research facilities and other overheads are not eligible for funding and must be absorbed by the researcher's host institution.

How Much Funding can a Proposal Receive?

This initiative will provide support to a maximum of $20,000 for individual proposals. Subject to review, the proposed total amount of funding for this initiative is $100,000. Funding allocations will be based on individually approved activities that meet the program's objectives.

How Long can the Project Last?

The anticipated start date of activities is August 15, 2005, and projects receiving funds can operate until March 31, 2006.

How will Proposals be Reviewed?

All proposals will be screened by NHPD staff to verify completeness, conformity and eligibility with specific attention being paid to the multi-disciplinary nature of the proposal, the proposed activities, and relevance to the funding priorities and objectives of the NHPRP. Proposals that do not meet these mandatory requirements will be rejected without further review.

Eligible proposals will be reviewed by NHPD staff in consultation with members of the Directorate's external Expert Advisory Committee (EAC) and experts from the scientific community at large, who are familiar with the relevant issues, represent a range of stakeholder interests, and are able to contribute to the assessment of proposals and awarding of funds.

The findings of the Expert Advisory Committee will become recommendations to the NHPRP and are subject to final approval by Health Canada.

Health Canada is under no obligation to provide funding or to enter into a contribution agreement as a result of this RFP, of the funding proposals submitted, or as a result of existing or previous funding agreements with an organization. Additionally, Health Canada reserves the right to:

• reject any or all proposals received in response to this RFP;
• accept any proposal in whole or in part;
• cancel, modify or re-issue this RFP at any time;
• verify any or all information provided by an organization as part of their proposal.

Audit Process (if proposal is funded)

Contribution agreements under the NHPRP are subject to a Risk-Based Audit Framework, which identifies the audit process to ensure that the expenditure of public funds is exercised with appropriate diligence. The NHPRP manager will monitor projects and determine which should be audited on the basis of risk.

Audits are planned and conducted to ensure that expenditures were made in accordance with terms and conditions of the contribution agreements, that specific non-financial terms and conditions are met, that the recipients were efficient in managing the agreement, and that the Crown received value for money. Audit arrangements, including coverage and scope, will be determined by Health Canada. In general, auditors will be appointed by the Department unless other arrangements are stipulated in the contribution agreement.

Intellectual Property

Agreements supporting successful proposals under this RFP will incorporate the following provision, in relation to intellectual property rights:

Any documentation produced by the recipient or third party in carrying out the obligations under the agreement shall vest in and remain the property of the recipient or the third party, unless otherwise agreed to. The Minister may require the recipient or third party to provide documents, if any, that have been produced under the contribution.

The Minister will have a non-commercial, non-exclusive, irrevocable, worldwide, fully-paid, and royalty-free license to use the intellectual property as he/she deems fit, including copying, translating, producing or further developing all documents for publication or for any other purpose, except sale or licensing in commercial competition with the recipient (and/or third party). The Minister's license also includes the right to disclose the components to other organizations for information purposes only.

Proposal Requirements

The proposal must be submitted in writing and contain the following (refer to page 3 of the application form):

• Standard cover letter;
• Project summary and rationale;
• Research proposal;
• Workplan with accurate timelines; and
• Detailed budget.

Administrative and Reporting Requirements (if proposal is funded)

Administrative requirements, such as financial and narrative reporting as well as other monitoring activities, will be established in a formal Contribution Agreement between Health Canada and the successful applicants. For all agreements, there is a requirement to:

• Submit quarterly activity and cash flow reports;
• Submit a final report;
• Participate in on-site visits as required.

Specific details of the accountability and reporting requirements will be outlined in the Contribution Agreement.

Application and Submission Details

Please use the Application Form that is attached with this RFP and submit to the address shown below. To be considered for funding, eligible applicants must provide all of the requested information as indicated on the application form.

The deadline for proposals is May 31, 2005. Only applications post-marked by the deadline will be accepted. It is the applicant's responsibility to ensure that the proposal is received on time.

For further information please contact:
Christine Cryan, Project Officer
Natural Health Products Research Program
Natural Health Products Directorate
Health Products and Food Branch
Health Canada
2936 Baseline Rd., Tower A
AL: 3302D
Nepean, ON K1A 0K9
Tel: (613) 941-5513
Fax: (613) 946-1615
Email: christine_cryan@hc-sc.gc.ca