Natural Health Products Research in Children and Youth: A Priority-Setting Conference (March 17-18, 2002, Toronto)

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Table of Contents

• Executive Summary
• Introduction
• Research Priorities, Strategies and next Steps
  • 1. Create a Usage Database and Evaluate Current Data on Nhps Relative to Children
  • 2. Explore Both Basic and Clinical Science Issues
  • 3. Set Priorities for Knowledge Translation and Transfer to Consumers
  • 4. Research Ethical Questions Related to the Health Care of Children, and Research Methodologies for the Study of Nhp Use in Children
• Conclusion
• Appendix A - Participants List
• Appendix B - Conference Agenda
• Appendix C - Summary of Presentations
• Appendix D - Research Priorities of Working Groups

Executive Summary

As part of its mandate to facilitate the research of natural health products (NHPs), and in keeping with its objective to foster collaboration and partnership building, the Natural Health Products Directorate (NHPD) at Health Canada continued its relationship with The Hospital for Sick Children Foundation by co-hosting a second conference on NHP research in children and youth on March 17-18, 2002. The participants included academics, researchers, paediatricians, practitioners of complementary and alternative health care (CAHC), parents and hospital administrators, as well as representatives from the NHP industry and various government agencies.

The conference participants were asked:

• to identify the current state of NHP-based research relative to children and youth;
• to facilitate dialogue and promote networking within and between the conventional and complementary and alternative health care communities; and
• to establish a research agenda and identify priorities that will assist in the development of the evidence base that will both provide Canadians with the information required to make informed decisions about NHPs and their use with children, and that will also support the regulatory framework proposed by the NHPD.

Through group and plenary discussions, the participants identified four research priorities to address these objectives.

1. Create a usage database and evaluate current data on NHPs relative to children. It would be helpful to identify the NHPs that are most commonly used by Canadian children and the conditions for which NHPs are most frequently used in the treatment of children, as well as to determine what research has already been done in this area.
   1. Undertake a national survey to determine who is using what products to treat which conditions, and to determine when and why they are using these products.
   2. Piggyback the national survey onto existing surveys such as the national census, the National Longitudinal Survey of Children and Youth (supported by Human Resources Development Canada) and similar existing surveys.
   3. Identify, synthesize and evaluate existing data on NHPs. Existing databases on NHPs should be evaluated to ascertain if they can provide useful information on NHP use by children. This evaluation might involve the use of systematic reviews and meta-analyses.
   4. Work with the Cochrane Collaboration, an international organization that prepares and maintains systematic reviews that the general populace can use to make more informed decisions about various health care therapies and products. The Cochrane Collaboration may be helpful since it already has fields or networks that pay particular attention to complementary medicine and child health.
   5. Establish a National Centre of Excellence (NCE) for NHPs and CAHC, with nodes established by geography and expertise. Local geographical needs and sensitivities would be considered, as would the expertise of various specialities and practices. Paediatrics would be one of the top three priorities for this NCE.
2. Explore both basic and clinical science issues. There are broad gaps in our knowledge of NHPs and their use by children and youth that can only be bridged by basic science and clinical research.
   1. Identify areas of high need and/or high prevalence of use. The health conditions that are most commonly encountered in paediatric care and the NHPs that are used most frequently by children should be the primary focus of preliminary research. Possible areas of investigation could include the pharmacokinetics of NHPs as well as drug-NHP interactions and NHP-NHP interactions.
   2. Build a basic science knowledge base. After identifying the diseases that should be the focus of research, the studies will seek answers to similar questions about the use of NHPs to treat specific diseases so that a matrix of information can be constructed.
   3. Collaborate, co-operate and communicate with existing networks, practitioners and NHP experts. Researchers studying NHPs and children should work with existing networks (e. g., the Canadian Paediatric Clinical Pharmacology Network) or partner with the Canadian Institutes of Health Research (CIHR) where research into NHPs and their use by children could fit into existing programs.
3. Set priorities for knowledge translation and transfer to consumers. Consumers want accurate and intelligible information on NHPs, especially when using these products with their children. They want to have confidence in both the products they take (with respect to efficacy, safety and quality) and in the information they receive (about product claims and content).
   1. Identify quality information on the Internet. Websites that provide monographs informed by the most recent evidence-based medical research on the more commonly used NHPs could appear on a list of approved sources of information. This could be part of an initiative, facilitated by the NHPD, to establish a central clearing house for information dissemination.
   2. Identify professionals who are knowledgeable about NHPs. While many people offer information and advice about NHPs, there is a wide range of expertise and competence. Only those who are knowledgeable should be dispensing and providing advice about NHPs.
   3. Accredit pharmacies and health food stores. Pharmacies and health food stores that have properly trained personnel onsite can be accredited as centres that provide quality information on NHPs. However, the impression must not be fostered that the NHPD is trying to regulate in an area of provincial jurisdiction.
   4. Educate the end consumer. To provide consumers with more and accurate information about NHPs, pamphlets and posters could be available in pharmacies, health food stores and the offices of health care professionals; curricula in high schools could be expanded; and public forums could be hosted.
4. Research ethical questions related to the health care of children and research methodologies for the study of NHP use in children. Policies that guide ethical research involving children need to be better developed. There is also a need to establish guidelines for NHP research that respect both accepted scientific methods and the various paradigms of NHP use.
   1. Review the Tri-Council Policy statement. After a review of the Tri-Council Policy statement governing the conduct of ethical research in humans, a companion document could be developed that would specifically address ethical concerns about research involving children.
   2. Review international law and policy. Since other jurisdictions may have already undertaken the task described above, a review of international law and policy could avoid unnecessary duplication and identify uniquely Canadian needs.
   3. Determine potential barriers to NHP research in children. Through consultation and surveys of paediatric research ethics boards (REBs) and various research councils (such as CIHR), potential barriers to NHP research with children could be identified. Having identified possible barriers, it would be possible to design strategies to resolve them.
   4. Start with the research methodologies that are known. There are accepted scientific research methodologies that could be applied to the research of NHP use in children, including randomized clinical trials. In addition, observational studies and epidemiological studies are both accepted methods and are adaptable to NHP research.
   5. Establish clinical trial research guidelines for children and youth. NHPs are often used in a specific cultural or paradigm context, and/or as part of individualized treatments that are not always easily adapted to randomized trials. The levels of evidence that have traditionally been accepted in CAHC research are often not the same as those for conventional medicine.

Experiences and opinions with considerable enthusiasm and goodwill. It was noted that research on NHP use in paediatric populations should also include the fetus, since the NHPs that a mother may take could also affect the unborn child. Several participants stressed that children and youth populations are often 'forgotten populations' in health care research. Too often, results from research completed on adults are simply extrapolated to this younger population.

Introduction

As part of its mandate to facilitate the research of natural health products (NHPs), and in keeping with its objective to foster collaboration and partnership building, the Natural Health Products Directorate (NHPD)¹ at Health Canada continued its relationship with The Hospital for Sick Children Foundation (HSCF)² by co-hosting a second conference on NHP research in children and youth on March 17-18, 2002. The first collaborative conference took place on November 30 - December 1, 2001 in Toronto and considered funding priorities for NHP research in children and youth.³

The March 2002 conference was held at the Metropolitan Hotel in Toronto, Ontario. The participants included academics, researchers, paediatricians, practitioners of complementary and alternative health care (CAHC), parents and hospital administrators, as well as representatives from the NHP industry and from various government agencies, including the National Research Council of Canada (NRC)⁴, the Therapeutic Products Directorate⁵ and the NHPD⁶. The conference was co-chaired by Michael J. Smith, Senior Advisor at the NHPD, and Sunita Vohra, a paediatrician and researcher at the HSCF in Toronto.

The objectives for the conference were threefold. The conference participants were asked:

• to identify the current state of NHP-based research relative to children and youth;
• to facilitate dialogue and promote networking within and between the conventional and complementary and alternative health care communities; and
• to establish a research agenda and identify priorities that will assist in the development of the evidence base that will both provide Canadians with the information required to make informed decisions about NHPs and their use with children, and that will also support the regulatory framework proposed by the NHPD.

Following welcoming remarks by Michael J. Smith of the NHPD and Gwen Burrows of the HSCF, the participants introduced themselves.⁷ To provide background information for the working sessions that would follow, a variety of speakers gave talks on the use of NHPs by children and youth, drawing on their particular expertise or experience. Allison McCutcheon of the Department of Botany at the University of British Columbia spoke on "Quality Control and Product Standard Research for NHPs," while Sunita Vohra offered insights from both her work as a paediatrician and as a clinical researcher. Christine Harrison, a bioethicist at The Hospital for Sick Children, spoke on "Natural Health Products and Children: The Ethics of Care and Research." Sydney MacInnis gave a parent's perspective, while Maureen Horne-Paul, a naturopathic doctor, provided the point of view of a CAHC practitioner. Each participant was provided with a hard copy of the presentations of the various speakers as well as a summary document.⁸ A brief summary of these presentations follows.

Key Issues in Paediatric Research

• There are differences in paediatric vs. adult absorption/distribution/ metabolism/excretion.
• There is the potential for different adverse reactions than those documented in adult populations.
• There are concerns about the potential long-term effects of exposure during times of peak growth and development.
• The paediatric population is a more vulnerable population.
• Working with a paediatric population raises issues of autonomy, informed consent/assent and patient compliance.

Key Issues for Natural Health Products Research

• Similar products can vary widely from brand to brand with respect to quality, constituents, concentration, standardization, dosage form or units, markers/marker content, plant species and parts used.
• 'Quality' tends to mean different things to different people, including the amount of the active ingredient present in the product; that the product is safe, efficacious and consistently manufactured; that the correct plants/parts were used; and/or that the product is pure.
• Product purity can be adversely affected by contamination (such as by microorganisms, heavy metals or pesticides) or by adulteration (i.e., the intentional addition of undeclared substances).
• Most adverse drug reactions are due to poor quality - e.g., when an incorrect plant is unintentionally substituted for the correct plant due to misidentification; or when the product contains contaminants or adulterants.
• Product potency is a complex issue when dealing with botanical medicines and other multi-ingredient products.
• Standardized products are products that have a consistent marker content, ensuring product consistency from batch to batch. However, markers are not necessarily the active ingredient(s) that give that product its therapeutic benefit. Different manufacturers might use different markers for the same product and, even when they use the same marker, they might standardize the product to different concentrations of the marker. Therefore, even with standardization procedures in place, the potency of products is not assured from brand to brand.
• Active ingredients are not identified for the majority of botanical medicines.
• Relevant biological activity assays are required to obtain meaningful measurements of potency.
• While the interaction between drugs and NHPs (particularly botanical medicines) is increasingly receiving attention, much more research needs to be completed.

Ethical Considerations

• The National Council on Ethics in Human Research (NCEHR)⁹ states that research involving children seeks knowledge that may protect children from harm, benefit individual children and/or benefit children as a group.
• Ethical values and principles at stake:
  • informed choice;
  • respect of various perspectives;
  • trust;
  • safety; and
  • justice.
• Ethical research includes the selection and achievement of morally acceptable ends, and the morally acceptable means to those ends.
• Guiding ethical principles:
  • respect for human dignity;
  • free and informed consent;
  • vulnerable persons;
  • privacy and confidentiality;
  • justice and inclusiveness; and
  • the balancing of harms and benefits.

Parent's Perspective

• Parents are often drawn to the use of NHPs for the care of their children because of a curiosity with natural healing and gaps in the care that conventional medicine can provide.
• Both forms of care have their successes and failures.
• The use of CAHC does not supplant or replace the use of conventional medicine; instead, CAHC complements conventional medicine.
• Parents are often left with the task of integrating conventional and CAHC therapies and products.
• Parents must often rely on other parents as well as on their own initiative and skill as they seek information on CAHC therapies and products, and must adapt their lifestyle to the new demands of alternative diets and practices.

Possible Research Priorities

• NHPs are used as much for health promotion as for the treatment of illness.
• Which NHPs are being used by whom to treat which conditions?
• There is a need for information on NHPs and children relative to use, access, costs and how NHP use affects the health of children.
• Which NHPs pose the greatest risk or potential for harm and the greatest potential for benefits?
• What are appropriate standards for quality and safety in NHPs, and how do these standards compare with those set for pharmaceutical products and drugs? Are the two sets of standards comparable?
• Do NHP research trials need the same scientific standards as those used for pharmaceuticals? What research methodology is appropriate?
• Do we have good endpoints for clinical trials in children: are they valid, reliable and sensitive to change?
• Should we continue to do systematic reviews and meta-analyses of CAHC therapies and products?
• What role should patient/consumer preferences play in setting research priorities?
• Why do consumers use NHPs with children? Are they well informed? How did they become informed? Were their sources of information of high quality?

After a morning of presentations followed by lunch, the facilitator reviewed the conference objectives and the steps by which the discussions would proceed. He noted that while the NHPD might not be able to act on every recommendation proposed by the participants, it was nevertheless important for each working group to provide clear and detailed advice for each of their proposals. The participants (including the presenters) then assembled into four pre-selected working groups. Each working group concurrently met for 90 minutes to consider a variety of priorities and options that would address the objectives that had been set for the conference. They eventually narrowed their proposals to a list of not more than five priorities. (The priorities suggested by each working group are recorded in Appendix D) During the plenary session that followed, a reporter from each group provided an overview of that group's priorities to the other participants. Through consultations with the participants, these priorities were consolidated into the following preliminary list of priorities.

Preliminary List of Priorities

1. Develop a usage database - what is being done by whom to treat what.
2. Evaluate the existing data on NHPs relative to children.
3. Determine the standardizations that need to be set for NHPs to enhance their quality.
4. Explore the basic science issues related to the use of NHPs with children, particularly with respect to:
   1. NHPs and drug interactions; and
   2. NHPs and pharmacokinetics.
5. Explore the clinical science issues related to the use of NHPs with children, particularly with respect to:
   1. clinical trials involving NHPs when there are no other recognized or accepted treatment for a particular condition;
   2. observational research at sentinel sites; and
   3. drug interactions and pharmacokinetics.
6. Set priorities for knowledge translation and transfer to consumers.
7. Research ethical questions related to the health care of children.
8. Monitor outcomes of initiatives to improve the quality, efficacy and safety of NHPs as well as the translation and transfer of information to enhance consumers' informed choice.
9. Research methodologies for the study of NHP use in children.
10. Research dosage considerations - i.e., the safe and therapeutic dosages for NHP use in children.

Final List of Priorities

On the second day of the conference, the participants voted to further consolidate and narrow their focus to four research priorities. These priorities were:

1. Create a usage database and evaluate current data on NHPs relative to children.
2. Explore both basic and clinical science issues pertaining to:
   1. drug interactions and pharmacokinetics;
   2. clinical trials involving NHPs when there are no other recognized or accepted treatment for a particular condition; and
   3. observational research at sentinel sites.
3. Set priorities for knowledge translation and transfer to consumers.
   
4. Research ethical questions related to the care of children, and research methodologies for the study of NHP use in children.

Working groups for each of these four research priorities were formed by participant self-selection. During the working session that followed, each working group devised strategies that would advance their particular priority. The opportunities and challenges that may be encountered in the implementation of each strategy were considered and discussed. A reporter from each group once again presented their work to the other participants during the subsequent plenary session.

In the third and final working session, the working groups discussed the 'next steps' that could be taken to implement each strategy that they had identified during the previous session. The working groups provided concrete and practical steps to guide the implementation of the various strategies that were chosen for the research priority that had been the focus of their attention. The 'next steps' were to provide a map that would describe who would be doing what, and when they would be doing it. Possible sources of funding (if applicable) were also to be identified.

The results of these deliberations are described in the remainder of this report. In the discussion that follows, each priority is introduced by background information describing the relevance of that priority. Strategies and possible next steps for advancing the proposal are then presented, sometimes in separate sections and sometimes blended into one discussion.

Research Priorities, Strategies and Next Steps

1. Create a Usage Database and Evaluate Current Data on NHPs Relative to Children

Background:

Prior to studying the efficacy, safety and quality of NHPs, it would be helpful to direct this research toward those NHPs that are most commonly used by Canadian children. It would also be helpful to know which conditions are most frequently treated with NHPs, either in conjunction with conventional therapies and products or with NHPs alone. Similarly, it would be prudent to review existing data on NHPs to determine what research has already been done, to avoid duplication of efforts. Has that research been sufficiently rigorous? Have adverse reactions occurred when particular NHPs are taken or used in certain ways?

Strategies:

1. Undertake a national survey to determine who is using what products to treat which conditions, and to determine when and why they are using these products. Initially, pilot surveys could be taken in physicians' offices (both general practitioners and paediatricians) and perhaps through the practices of midwives and obstetricians, and in selected paediatric hospitals. Once the survey has been piloted and validated, a national survey could be undertaken at selected sentinel sites (such as clinics in paediatric hospitals and public health clinics where larger numbers of children are treated), at pharmacies (using touch screen info kiosks) and in commercial establishments where end-users are purchasing products. This surveying could be extended to include CAHC practitioners, specialty magazines (e.g., parenting magazines) and trade shows.

The survey would involve various stakeholders in the process of NHP research. It would help to raise public awareness of NHPs, and the purpose and results of the survey could be publicized through both scientific and popular media. To achieve results that are as representative of the Canadian population as possible, the researchers must be careful to ensure that the selection of participating sites does not inadvertently pre-select the data (i.e., avoid selection bias). They must verify that respondents are willing to disclose information on the survey, especially when the surveys are administered in practitioners' offices, since many users of NHPs do not routinely divulge this information to their physicians. The surveys would need to be constructed in a way that is culturally sensitive, and their administration and collection would require close coordination. The cost of such a national survey could be considerable.

2. Piggyback the national survey onto existing surveys such as the national census, the National Longitudinal Survey of Children and Youth¹⁰ (supported by Human Resources Development Canada¹¹ ) and similar existing surveys. By employing these already well-established surveys, it would be possible to collect information on a continuous and reliable basis. It would also be possible to study phases in NHP use and to focus on specific topics of interest. As is often the case, gaining funding for such an initiative might prove challenging.

3. Identify, synthesize and evaluate existing data on NHPs. Databases on NHPs that already exist should be evaluated to ascertain if they can provide useful information on NHP use by children and youth. Databases such as the Pharmacist's Letter¹² and NAPRALERT (NAtural PRoducts ALERT¹³ ) could be assessed, since they are well referenced; are updated daily; consider dosage range, efficacy and contraindications; and translate research published from other languages. Other databases that might be reviewed include the Lawrence Review of Natural Products.

Since an enormous amount of information would need to be evaluated and synthesized, this might require people who are particularly skilled in information technology as well as the use of systematic reviews and meta-analyses. A virtual network and/or coordinating centre could harness the skills and efforts of many experts in these fields. It might also be possible to partner with similarly interested groups, particularly scientific journals that occasionally seek review articles.

However, since these databases can only be fully accessed by subscription, there would be certain costs involved. Some databases and reviews are more user-friendly than others and it would require varying degrees of skill and expertise to successfully navigate them for our purposes. Public access to databases on NHPs and their use in the health care of children could help Canadians to make more informed choices. As just mentioned, these databases are often accessible through subscription only and are usually written in highly technical language that is intelligible only to experts. Consequently, these factors would normally place the databases beyond the grasp of most consumers. These concerns are discussed later in this report in the section on information translation and transfer (see pages 14-15). A further concern involves the ownership of the data. There may be proprietary rights and/or licensing concerns that prevent data, once retrieved, from being published or used in the desired way. It is noted that in Europe and the USA, these matters are being addressed through legislation that governs disclosure.

4. Possible collaboration with the Cochrane Collaboration merits particular comment.¹⁴ The Cochrane Collaboration is an international organization that prepares and maintains systematic reviews that the general populace can use to make more informed decisions about various health care therapies and products. It has fields or networks that pay particular attention to complementary medicine¹⁵ (under the direction of Dr. Brian Berman at the University of Maryland School of Medicine) and child health¹⁶ (coordinated by Dr. Terry Klassen, Chair of the Department of Paediatrics at the University of Alberta in Edmonton). Since these fields or networks of the Cochrane Collaboration would support collaborative review groups, it may be possible to forge a partnership with them. Such an undertaking would increase positive interactions between members of the Cochrane Collaboration and CAHC practitioners and researchers. It would permit the systematic review and evaluation, by an existing network of experts, of current data on NHP use by children and youth. Where appropriate, additional systematic reviews and meta-analyses could be undertaken.

Next Steps:

1. Establish a National Centre of Excellence (NCE) for NHPs and CAHC, with nodes established by geography and expertise. Local geographical needs and sensitivities would be considered, as would the expertise of various specialities and practices. Paediatrics would be one of the top three priorities for this NCE. This recommendation would be directed at networks of practitioners, funding agencies, universities, hospitals, industry and the general public. By working with a broad base of stakeholders - viz., researchers, practitioners and consumers - and by forming links with national organizations (e.g., the Canadian Paediatric Society), awareness of the work and goals of this NCE would be increased. The NCE would establish review criteria for its database, enhance research capacity via training and education, and contribute to knowledge transfer.

It is envisioned that seed money might be derived from the NHPD with ongoing funding coming from CIHR.¹⁷ Matching funding might be accessed from local foundations. The NCE should be structured in such a fashion that corporations can make tax-deductible donations to its work.

Establishing this NCE within six months to one year would be the first priority. It is hoped that a database could be functional within one year.

2. Do an environmental scan to identify existing databases. This task could be undertaken by the NHPD and Health Canada. The scan would identify existing data on NHPs as well as interested and qualified individuals. By completing such an environmental scan, it would be possible to avoid duplicating previous efforts and to identify when these efforts have not sufficiently encompassed the unique needs of Canadians.

This undertaking could be one of the first projects of the NCE described above. For the data gleaned by this scan to remain current and comprehensive, ongoing review and monitoring would be necessary.

2. Explore Both Basic and Clinical Science Issues

Background:

There are broad gaps in our knowledge of NHPs and their use by children and youth, which can only be bridged by basic science and clinical research. Some of these gaps relate to the pharmacokinetics of NHPs in general, but particularly when they are used by children. Other knowledge gaps include the interactions between NHPs and drugs, and even between NHPs and other NHPs, since these are not well studied or understood. Basic science and clinical research needs to be undertaken in a systematic fashion to set priorities and close the gaps.

Strategies:

1. Identify areas of high need and/or high prevalence of use - i.e., areas of paediatric health care that have particularly high needs, and NHPs that are used most frequently. The health conditions that are most commonly encountered in child and youth health care should be a primary focus of preliminary research. This initial research can lead to more exacting clinical trials that will be more rigorous. Possible areas of investigation could include the pharmacokinetics of NHPs as well as drug-NHP and NHP-NHP interactions.

Next Steps: Establish the criteria for deciding key areas of research. The following criteria might be considered. The more criteria that are met by a particular area of high need or high prevalence, the higher priority that area of research merits.

• prevalence of condition
• NHP utilization
• burden of illness (individual, familial, socioeconomic, etc.)
• efficacy of current therapy
• existing interest / research capacity / funding potential

The development of research criteria also aids funders to identify priorities when requests for proposals are made.

Based on these criteria, four areas of clinical concern were suggested as the focus of preliminary research: inflammatory diseases, infectious and immune diseases, respiratory diseases and mental illnesses.

2. Build a basic science knowledge base. After choosing to focus on four highly prevalent conditions - i.e., inflammatory diseases, infectious/immune diseases, respiratory diseases and mental illnesses - it would be possible to create a matrix showing information that would be sought through research. For each of these conditions, the following questions or areas of research could be the focus of efforts, thereby creating the matrix of information that is constructed in the following figure.

• What is the quality of the NHPs used to treat the condition?
• What formulations are used and which are more effective?
• What is the most efficacious dosage?
• Are there safety and toxicological issues; are there harmful interactions that must be considered; can too large a dosage be toxic?
• What are the pharmacokinetics of the product?
• How does the product affect the metabolism of the patient with the disease?
• What is the mechanism of action of the product?
• Who is using the product and for what conditions; how effective is it?
• Have clinical trials tested this product for this condition?
  
• How is the product being utilized?
• Is information on the product available to consumers?
• Has there been a synthesis of data concerning this product relative to this condition, and if so, where?
• Does the use of this product for the treatment of this condition raise any ethical questions?

View the Figure 1: Basic Science and Clinical Research Matrix

Next Steps:

Use the matrix and the aforementioned research criteria to identify high burden / high prevalence areas.

3. Collaborate, co-operate and communicate with existing networks, practitioners and NHP experts. Researchers who are studying NHPs and children should work with existing networks - e.g., the HIV/AIDS clinical trials network and the Canadian Paediatric Clinical Pharmacology Network (CPCPN). The CPCPN was recently established as a network linking six universities across Canada (UBC, Manitoba, Western, McMaster, Toronto and Montreal). It is comprised of experts in drug research involving children.

Attempts to forge such collaborations may raise issues concerning the credibility of NHP research and the role of NHPs in patient care, and may expose the tensions that can exist when different therapeutic cultures, agendas and paradigms come into contact with each other. However, because consumers/patients are using NHPs in increasing numbers, there is a need to study the safety and efficacy of these products. Even if some practitioners are uncomfortable with or are uncertain about the use of NHPs, it was the view of the conference participants that this reticence could not preclude the study of these products.

It will be challenging to build the research teams that can properly advance all three strategies listed above. Moreover, as before, acquiring sufficient funding could also be problematic. Nevertheless, the opportunities to conduct more comprehensive and advanced research, to foster greater co-operation and communication, and to improve our knowledge of NHPs significantly outweigh these concerns. There is tremendous public interest and support for research in this area, including support from some high profile champions. And there is an increasing willingness in many funding agencies and foundations (such as The Hospital for Sick Children Foundation) to fund and/or support NHP research.

Next Steps: Immediately undertake collaborative ventures. The CPCPN is meeting in April, 2002. A participant from this conference will be attending,

Next Steps: Partner with CIHR institutes where research into NHPs and their use with children and youths can fit into existing programs.

Next Steps: Consider the establishment of a National Centre of Excellence. To assist this endeavour, a workshop should be held that would assist its participants:

• to frame a NCE proposal;
• to identify appropriate themes (NHP, CAHC, Paediatrics); and
• to identify groups that could be partners in the application.
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3. Set Priorities for Knowledge Translation and Transfer to Consumers

Background:

Consumers want accurate and intelligible information on NHPs, especially when it comes to the use of these products with their children. They want to have confidence in both the products that they take (with respect to efficacy, safety and quality) and in the information that they receive (about product claims and content). There is concern that sources of credible information are scarce or difficult to access or understand, while some easily accessed sources may provide inaccurate information. The needs of the consumer - the end user - must be considered when products are designed.

Strategies:

1. Identify quality information on the Internet. The Internet has the potential to be a source of reliable and credible information in user-friendly language that the general public can understand. Some websites provide monographs, informed by the most recent evidence-based medical research, on the more commonly used NHPs. Sites that provide this level of quality service could appear on a list of approved sources of information. This would distinguish these sites from those that provide less credible information or use technical language that is difficult for the average consumer to understand.

2. Identify professionals who are knowledgeable about NHPs. While many people offer information and advice about NHPs, there is a wide range of expertise and competence. Only those who are knowledgeable should be dispensing and providing advice about NHPs. This is particularly true when concerns exist about interactions between prescription drugs and NHPs, or between over-the-counter drugs and NHPs. Continuing education courses should be available for professionals, such as pharmacists, to keep them abreast of current data on NHPs. Information from current research should be 'translated' into readily understood language and disseminated to professionals, consumers and manufacturers alike. This process should be information-driven rather than market-driven. Admittedly, such a proposal would have to overcome financial challenges and obstacles to information transfer.

3. Accredit pharmacies and health food stores. Pharmacies and health food stores that have properly trained onsite personnel can be accredited as centres that provide quality information on NHPs. Existing initiatives by the Canadian Pharmacist's Association and the Canadian Health Food Association (CHFA)¹⁸ to educate their memberships concerning NHPs should be encouraged to continue.

Several challenges could arise with this strategy. A curriculum would need to be developed to ensure that personnel (whether in pharmacies or health food stores) are properly trained, and such accreditation would need to win the acceptance of both providers and consumers. Furthermore, the impression must not be fostered that the NHPD is trying to regulate in an area of provincial jurisdiction. Finally, such an undertaking could be costly, and it is not clear where funds would be obtained.

4. Educate the end consumer. To provide consumers with more and accurate information about NHPs, a number of venues could be used to disseminate quality information. Pamphlets and posters could be available in pharmacies, health food stores and the offices of health care professionals. Curricula in high schools that teach students about health could be expanded to include the potential benefits and risks of NHPs. Community forums could also be a venue where information could be provided to the public.

Finding sites that are both appropriate and willing to participate could be challenging. Such a program could be costly, and would not likely have ready and obvious benefits. The literature must be written in such a way that generic products are discussed rather than specific brands or lines.

Next Steps:

1. Establish a central clearing house for information dissemination. Information endorsed by Health Canada would be made available to consumers via an Internet site and via brochures and information sheets that would be distributed to health care professionals, health food stores, pharmacies, community health centres, etc. The creation of a central clearing house would be facilitated by the government, in partnership with industry, the CHFA, professional associations (pharmacists, CAHC professionals, etc.) and professional societies. Advertisements in the media would alert the public to the existence of a central clearing house that is providing credible, accurate and intelligible information on NHPs.

Within the next six months, partners for this project could be identified and the infrastructure necessary for its activation could be created. Information that would be disseminated to the public could be organized during the next year.

2. Actively promote accreditation process. While the creation of a central clearing house of information is a more passive process, the accreditation of individuals who are knowledgeable in information concerning NHPs would require active outreach. By attending and speaking at professional conferences, tradeshows and public events about the benefits of accrediting certain individuals who are knowledgeable in NHPs, it would be possible to stimulate interest in this type of certification. Consumers would prefer to consult properly trained and certified personnel, and providers such as pharmacists and health store employees would recognize an opportunity to promote their services. Such accreditation would be completely voluntary, and could become part of professional continuing education requirements. It is expected that it would take approximately one year to design and implement such an accreditation process.

4. Research Ethical Questions Related to the Health Care of Children, and Research Methodologies for the Study of NHP Use in Children

Two groups of participants came together to discuss two separate topics. Consequently, strategies one, two and three focus on ethics, while strategies four and five focus on research methodologies.

Background:

The Tri-Council Policy statement for ethical research in humans already exists and must be taken into account when NHP research involving humans is proposed.¹⁹ However, the section of that policy that deals with ethical research involving children is not well developed. Helping to improve and expand this section would be a worthwhile endeavour, with specific attention being paid to the issues relevant to CAHC.

There is a need to establish guidelines for NHP research that both respect accepted scientific methods and the various paradigms of NHP use. It is often stated that the manner in which NHPs are sometimes used in older, more traditional therapies makes it difficult (if not impossible) to evaluate NHPs by the current gold standards of recognized scientific research (although this concern is not unique to NHPs). Consequently, those who hold this view suggest that new methods for the study of NHPs must be developed. Presumably, similar concerns would be raised for the study of NHP use in children.

Strategies:

1. Review the Tri-Council Policy statement. After a review of the Tri-Council Policy statement governing the conduct of ethical research in humans, a companion document could be developed that would specifically address ethical concerns pertaining to research involving children. The companion document would focus on the 'best interests of the child,' although such interests can, admittedly, be difficult to define.

2. Review international law and policy. Other jurisdictions may have already undertaken the task described in the first strategy. Accordingly, a review of international law and policy could avoid unnecessary duplication. However, it would be necessary to evaluate any international laws and policies in terms of the unique needs of Canadians.

Next Steps for strategies 1 and 2: The Hospital for Sick Children Foundation and the NHPD could facilitate the creation of a working group and a larger advisory group of relevant stakeholders (including conventional and CAHC practitioners, and representation from the National Council on Ethics in Human Research and the Canadian Paediatric Society²⁰ ). The HSCF would fund this project, including the costs of hiring a research assistant and a consultant to write the document, and the costs of meetings of the group members. The project would require at least one year to complete.

3. Determine potential barriers to NHP research in children. Through consultation and surveys of paediatric research ethics boards (REBs) and various research councils (such as CIHR), potential barriers to NHP research with children could be identified. Having identified possible barriers, it would be possible to design strategies to resolve them.

Next Steps:

The NHPD would encourage academic researchers to develop a team of experts in NHPs, research with children, and survey research to develop and submit a grant application to CIHR.

4. Start with known research methodologies. There are accepted, scientific research methodologies that could be applied to the research of NHP use in children, including randomized clinical trials. In addition, observational studies and epidemiological studies are both accepted methods and are adaptable to NHP research. Existing research methodologies, including international sources, should be reviewed for appropriate strategies. As always, research methods must place patient safety first and must use valid and reliable outcome measures.

5. Establish clinical trial research guidelines for children and youth. Through consultation with paediatric REBs, CIHR, and the Tri-Council, methods to access information could be developed. There are a number of challenges that would need to be considered when research methods and guidelines are designed. Like some conventional health care research, treatments involving NHPs are often part of a multi-treatment therapeutic approach. NHPs are often used in a specific cultural or paradigm context, and/or are part of individualized treatments that are not easily adapted to randomized trials. There is ongoing debate/discussion concerning the levels of evidence that have traditionally been accepted in CAHC research, since these are often not the same as those for conventional medicine.

Conclusion

During the working and plenary sessions, the participants shared their expertise, experiences and opinions with considerable enthusiasm and goodwill. It was noted that research on NHP use in paediatric populations should also include the fetus since the NHPs that a mother is taking could also affect the unborn child. Several participants stressed that children and youth populations are often 'forgotten populations' in health care research. Too often, results from research completed on adults are simply extrapolated to this younger population.

At the end of the second day, Michael J. Smith from the NHPD and co-chair of the conference, thanked the participants for their hard work and useful contributions. He welcomed the many recommendations that had been made during the two days of discussions, while acknowledging that not all of them fell within the jurisdiction of the NHPD. Nevertheless, he reassured the participants that the information and ideas generated during the conference would be reviewed with great interest, would be disseminated to the appropriate parties and would form the basis for further endeavours by the NHPD.

Gwen Burrows of The Hospital for Sick Children Foundation - a co-sponsor of the conference - also expressed her gratitude to the participants and noted that the HSCF appreciates the contribution that this conference will make to the foundation's goals of supporting paediatric care, research and education.

Appendix A - Participants List

Walid Aldoori
Whitehall-Robins
Mississauga, Ontario

Susan Baker
American Academy of Paediatrics
Children's Hospital of Buffalo
Buffalo, New York

Lola Baydala
Misericordia Child Health Clinic
Edmonton, Alberta

John Burgess
Rockingham Pharmasave
Halifax, Nova Scotia

Peter Chan
Health Canada
Ottawa, Ontario

Lawrence Cheng
Chamber of Chinese Herbal Medicine of Canada
Toronto, Ontario

Michael Cheng-Che Chung
Amber TCM Healing Centre
West Vancouver, British Columbia

Tammy Clifford
CHEO Research Institute
Ottawa, Ontario

Joan Gilmore
Osgoode Hall Law School
Toronto, Ontario

Tutti Gould
Hylands Homeopathic Canada
Sutton, Quebec

Christine Harrison
The Hospital for Sick Children
Toronto, Ontario

Maureen Horne-Paul
Naturopath
Kingston, Ontario

Melissa Johnson
Health Canada
Ottawa, Ontario

Francois Jooste
Natural Health Clinic
Smithville, Ontario

Bonnie Kaplan
University of Calgary
Calgary, Alberta

Sid Katz
University of British Columbia
Vancouver, British Columbia

Valérie Lanctot-Bedard
Guilde des Herboristes
Canadian Coalition of Herbal Associations
South Stukely, Quebec

Sydney MacInnis
Parent
Toronto, Ontario

Robin Marles
Brandon University
Brandon, Manitoba

Doreen Matsui
Canadian Paediatric Society
Children's Hospital of Western Ontario
London, Ontario

Siddika Mithani
Health Canada
Ottawa, Ontario

David Moher
Children's Hospital of Eastern Ontario Research Institute
Ottawa, Ontario

Nancy Morse
Nutricia Canada Inc
Kentville, Nova Scotia

Doug Richardson
Parent
Aurora, Ontario

Michael Rieder
Children's Hospital of Western Ontario
London, Ontario

Paul Saunders
Canadian College of Naturopathic Medicine
North York, Ontario

Jackie Shan
CV Technologies Inc
Edmonton, Alberta

Planning Team

Irma Boyle
Health Canada
Ottawa, Ontario

Gwen Burrows
The Hospital for Sick Children Foundation
Toronto, Ontario

Allison McCutcheon
University of British Columbia
Vancouver, British Columbia

Michael J. Smith
Health Canada
Ottawa, Ontario

Sunita Vohra
The Hospital for Sick Children
Toronto, Ontario

Facilitator:
Dennis O'Hara
Toronto, Ontario

Appendix B - Conference Agenda

Sunday, March 17th

9:00 a.m.

Welcome from the Natural Health Products Directorate
Michael J. Smith
NHPD

Welcome from the Hospital for Sick Children Foundation
Gwen Burrows
HSCF

9:20 a.m.

Introductions (all participants)
Facilitator assisted

Keynote Presentations

10:00 a.m.

Quality Control & Product Standard Research for NHPs
Allison McCutcheon
University of British Columbia

10:30 a.m.

Break

10:50 a.m.

Conventional Health care Provider & Researcher perspectives
Sunita Vohra
Hospital for Sick Children

Views from the field....

11:20 a.m.

Bioethics Perspective
Christine Harrison
Hospital for Sick Children

Parent Perspective
Sydney MacInnis

CAHC Practitioner Perspective
Maureen Horne-Paul
Naturopathic Doctor

12:30 p.m.

Lunch: provided on site

1:30 p.m.

First Working Group Session - Establishing the Priorities
Each group will identify priorities for developing a research agenda for the study of the use of NHPs by children and youth. See the Group List to determine which group you are in. Also, see Instructions for 1^st Working Session.

3:00 p.m.

Break

3:20 p.m.

First Plenary Session
Facilitator
Each group reports. The goal will be to construct a single list of 4 to 6 priorities derived with the consensus of all participants.

4:30 p.m.

Invitation to Reception
Gwen Burrows

First day questionnaire
Facilitator
Each participant is asked to complete a quick questionnaire before attending the reception. The questionnaire should only take a minute or two to finish.

Monday, March 18th

9:00 a.m.

Re-cap of first day
Sunita Vohra

9:15 a.m.

Second Working Group Session - Establishing the Strategies
Participants self-select into the priority of their interest. Each group will propose strategies for addressing their priority. See Instructions for 2^nd Working Group

10:45 a.m.

Break

11:00 a.m.

Second Plenary Session
Facilitator
Each group reports. The goal will be to construct a short list of preferred strategies for each research priority.

12:30 p.m.

Lunch: provided on site

1:30 p.m.

Re-cap of where we're at
Facilitator

1:40 p.m.

Third Working Group Session - Identifying the Next Steps
Participants self-select into the strategy of their interest to determine the next steps to take to implement that strategy. See Instructions for 3^rd Working Group Session.

2:45 p.m.

Break

3:00 p.m.

Third Plenary Session
Facilitator
Each group will have 7 minutes to report on the next steps it has identified.

4:00 p.m.

Concluding Remarks
Michael J. Smith and Sunita Vohra

Conference Adjourns
participants complete short questionnaire

Appendix C - Summary of Presentations

Conference Objectives

1. Identify the current state of NHP based research relative to children and youth.
   
2. Facilitate dialogue and promote networking within and between the conventional and CAHC communities
   
3. Establish a research agenda and identify priorities that will assist in the development of the evidence base that will both provide Canadians with the information the need to make informed decisions about NHPs and their use by children, as well as support the regulatory framework proposed by the Natural Health Product Directorate.

Key Issues in Paediatric Research

• Differences in absorption/distribution/ metabolism/excretion
• Potential for different adverse reactions than those documented in adult populations
• Concerns about potential long-term effects of exposure during time of peak growth and development
• Vulnerable population
• Autonomy
• Informed consent/assent
• Compliance

Key Issues for Natural Health Products

• Similar products can vary widely with respect to quality,
• constituents, concentration, standardization, dosage form or units, markers/marker content, plant species and parts used.
• Quality can mean the amount of the active ingredient; that the product is safe, efficacious and consistently manufactured; that the correct plants/parts were used; that the product is pure.
• Most adverse drug reactions are due to poor quality - i.e., when the wrong substitution is made, or when the product contains contaminants or adulterants.
• Product potency is a complex issue when dealing with botanicals and other multi-ingredient products.
• Standardized products are products that have a consistent marker content, ensuring product consistency from batch to batch.
• Potency is the amount of active ingredient required to obtain the desired therapeutic effect.
• Active ingredients are not identified for the majority of herbs.
• Relevant biological activity assays are required to obtain meaningful measurements of potency.

Ethical Considerations

• National Council on Bioethics in Human Research (NCBHR): research involving children seeks knowledge that may protect children from harm, benefit individual children, and/or benefit children as a group.
• Ethical values and principles at stake:
  • informed choice;
  • respect of various perspectives;
  • trust;
  • safety; and
  • justice.
• Ethical research includes the selection and achievement of morally acceptable ends, and the morally acceptable means to those ends
• Guiding ethical principles:
  • respect for human dignity
  • free and informed consent
  • vulnerable persons
  • privacy and confidentiality
  • justice and inclusiveness
  • the balancing of harms and benefits

Possible Research Priorities

• NHPs are used as much for health promotion as the treatment of illness.
• What is being used; by whom; for what?
• Need for info re: use, access, costs, how NHPs affect quality of health in children.
• Which NHPs pose the greatest risk or potential for harm?
• What are appropriate standards for quality and safety in NHPs and how do these compare with the standards set for pharmaceuticals; are the two sets of standards comparable?
• Do NHP research trials need the same scientific standards as used for pharmaceuticals?
• Do we have good endpoints for clinical trials in children; are they valid, reliable and sensitive to change?
• Should we continue to do systematic reviews and meta-analyses?
• What role should patient/consumer preferences play in setting research priorities?
• Why do consumers use NHPs with children; are they well informed; how did they become informed; were their sources of information of high quality?
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Appendix D - Research Priorities of Working Groups

Group 1 - Red Group

1. Clinical Research
   1. focus on NHPs being used now to set priorities
   2. pilot projects for key areas to begin research
   3. where there is no other identified treatment and the illness is severe
   4. quality of NHPs used in clinical research
   5. need to build research capacity too - clinical research skills and understanding of issues involved with NHP research
2. Knowledge Transfer and Information (Informed Choice)
   1. labelling = selection of NHPD role in informed choice
   2. where people get information
   3. why people use what they use
   4. allowing people to use info appropriately
   5. database
3. Interactions
   1. drug - NHP
   2. NHP - NHP
   3. food - NHP
   4. communication/reporting of adverse reactions or interactions
4. Dosage Considerations
   1. determining safe dosages
   2. determining therapeutic dosages
   3. determining dosage used in clinical practice
5. Research Methodology
   1. multi-approach treatments
   2. cultural context
   3. individualized treatments
   4. role/challenges of conventional research paradigm and NHP use
   5. comparison of diagnosis from various healing paradigms
   6. different levels of evidence between paradigms

Group 2 - Blue Group

1. Do Clinical Research
   1. dosage spread
      1. what is the safe range for children and youths
      2. how do we or can we extrapolate from adults to kids
   2. do observational research on a global scale
      1. to form the basis for future clinical trials
   3. Research Ethics Boards
      1. what do they know/believe
      2. how do they assess protocols that don't 'fit' their ideas of 'best research methods'
   4. collect information from some key sites where many children are treated
2. What are the standardization needs:
   1. Markers
   2. how reliable are international standards and studies?
3. Identify and assess existing data and create a database:
   1. synthesize current knowledge
   2. create database of expertise, info about plant materials, existing research, etc.
   3. develop a concise compendium of key research ideas
   4. what can we learn from what others have already done?
   5. develop good usage data - what is being used by Canadian children?
4. Knowledge transfer:
   1. where do consumers get their information?
   2. how reliable is that information?
   3. what do we mean by informed choice?
   4. what do conventional practitioners know; how effectively are they informing and communicating?
   5. review of labelling in paediatrics
5. Do Basic Science Research:
   1. pharmokinetics, especially with respect to children and NHPs

Group 3 - Green Group

1. Efficacy and effectiveness - What are people doing/using?
2. How to evaluate the quality of existing evidence:
   1. can evidence be extrapolated from adults to children?
   2. does the required evidence/data already exist?
   3. ssues of quality, assessment and transparency must be resolved.
3. Stimulate research if it is warranted
4. Transfer information to youth, parents and practitioners
5. Work with an open, expanded mind-set

Group 4 - Yellow Group

1. Identify and assess extant data
2. Do an environmental scan - What products are being used? What conditions are being treated? etc.
3. Do qualitative studies: decision making, information needs (all stakeholders)
4. Do scientific evaluation of the quality, safety and efficacy:
   1. clinical Studies level of evidence required to approve a clinical trial
      1. quality
         1. standards for quality
         2. tests and standards for identity, purity and potency
      2. safety
         1. must have full toxicology data, unless adequate safety data in adults and no reason to believe different effects in children
      3. efficacy
   2. basic science
      1. mechanisms of action
      2. NHP-drug interactions, NHP-NHP interactions, etc.
5. Monitor outcomes

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