Joanne Barnes BPharm PhD MRPharmS FLS Associate Professor in Herbal Medicines School of Pharmacy

1. Improving the quality of reporting of randomized controlled trials evaluating herbal interventions: Implementing the CONSORT statement • Joel J. Gagnier ND, MSc1, Heather Boon PhD2, Paula Rochon MD, MPH3, David Moher MSc4, Joanne Barnes5, Claire Bombardier MD6 for the CONSORT group • 1. Address: 5955 Ontario St, Unit 307, Windsor, Ontario, Canada, N8S1W6. • 2.  Address: Faculty of Pharmacy, 19 Russell Street, University of Toronto, Toronto, Ontario, Canada, M5S 2S2. • 3.  Address: Baycrest Centre for Geriatric Care 3560 Bathurst Street, Toronto, Ontario, Canada, M6A 2E1. • 4.  Address: Children’s Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Rm. 139, Ottawa, Ontario, Canada, K1H 8L1. • 5.  Address: Centre for Pharmacognosy & Phytotherapy, School of Pharmacy, 29/39 Brunswick Square, University of London, London, United Kingdom, WC1N 1AX. • 6.  Address: Institute for Work and Health, 481 University Avenue, Suite 800, Toronto, Ontario, Canada, M5G 2E9. Joanne Barnes BPharm PhD MRPharmS FLS Associate Professor in Herbal Medicines School of Pharmacy Faculty of Medical and Health Sciences University of Auckland Auckland j.barnes@auckland.ac.nz

2. Improving quality of descriptions of herbal medicine interventions in published reports Gagnier JJ, Boon H, Rochon P, Moher D, Barnes J, Bombardier C for the CONSORT group. Ann Intern Med 2006;144:364-367 Gagnier JJ, Boon H, Rochon P, Moher D, Barnes J, Bombardier C for the CONSORT group. J Clin Epidemiol 2006;59:1134-1149

3. Background • In health-care, randomised clinical trials (RCTs) are the gold standard for assessing the efficacy of interventions • Biased results from poorly designed or reported trials can mislead decision making • Identifying bias demands complete and accurate reporting of trials • CONSORT guidelines (Two-arm parallel): 22 item checklist and a flow-chart • Apply to all controlled, two arm, parallel trials • Are extensions (e.g., reporting clustered trials) and context specific elaborations (e.g., reporting harms)

4. CONSORT Checklist

5. CONSORT Checklist Moher et al for the CONSORT Group. Ann Intern Med. 2001;134:657-62. Altman et al for the CONSORT Group. Ann Intern Med. 2001;134(8):663-94.

6. A wide range of herbal medicinal products is available . . . • Solid dosage forms: tablets, capsules, including multi-herb, herb-vitamin/mineral products • Semisolid: creams, ointments • Liquid dosage forms: tinctures • Crude herbs • Chinese ‘herbal’ patent medicines • etc Image from European Herbal Practitioners Association website

7. Herbal medicines are chemically rich complex mixtures Tablets containing extract of St John’s wort herb Contain: • Hyperforin, adhyperforin, hypericin, pseudohypericin, isohypericin, protohypericin, protopseudohypericin, kaempferol, quercetin, luteolin, hyperoside, isoquercitrin, quercitrin, rutin, biapigenin, amentoflavone, catechins, tannins, other phenols etc etc • (excipients) Aspirin tablets Contain: • Aspirin • (excipients)

8. Herbal medicines have a variable composition • Numerous different chemical constituents: hundreds! • Specific constituents often unknown or only partly explained; constituents responsible for effects often unknown • Constituents differ with plant part (e.g. root, leaves) • Other factors affect the profile of constituents in herbal material • environmental factors, eg climate, growing conditions, time of harvest • post-harvesting factors, eg storage conditions, processing, type of extract etc • standardisation for certain constituents is possible • few products standardised to known active constituent(s) • batch-to-batch and manufacturer-to-manufacturer variation occur • Other quality problems • intentional/accidental botanical substitution: wrong/different species • Intentional/accidental adulteration: e.g prescription medicines – corticosteroids etc

9. Echinacea (E. purpurea, E. pallida, E. angustifolia) • 3 species used medicinally • black sampson; purple coneflower (E. purpurea); pale coneflower (E. pallida) • part used: rhizome, root; aerial parts (herb) of E. purpurea • key constituents: alkylamides, phenylpropanoids, polysaccharides, volatile oil • constituents differ between the different species and plant parts

10. Barnes J, Anderson LA, Gibbons S, Phillipson JD. Echinaceaspecies (Echinacea angustifolia (DC.) Hell., Echinacea pallida (Nutt.) Nutt., Echinacea purpurea (L.) Moench): a review of their chemistry, pharmacology and clinical properties. J Pharm Pharmacol 2005;57:929-954 What is “Echinacea”?

11. Herbal products containing the same herbal ingredient(s) but made by different manufacturers are not identical • Profile of constituents in different manufacturers’ products varies • Analytical study of 8 St John’s wort products - hyperforin content: 0.01% to 1.89%; at least 1% required for clinical efficacy - hypericins content: 0.03% to 0.29%; 57 to 130% of amount stated on label De Los Reyes G, Koda RT. Am J Health-Syst Pharm 2002;59:545-7 • Several other studies with other herbal products. See www.consumerlab.com • Differences in bioavailability of standardised ginkgo products. Kressmann S et al. Pharmaceutical quality of different Ginkgo biloba brands. J Pharm Pharmacol 2002;54:661-669 Kressmann S et al. Influence of pharmaceutical quality on the bioavailability of active components from Ginkgo biloba preparations. J Pharm Pharmacol 2002;54:1507-1514 • Evidence for safety (and efficacy) is product- or extract-specific

12. Herbal medicines • Many reports of trials (and other experiments) do not adequately describe the herbal preparations tested • Impossible to replicate experiments • Difficult to interpret findings in context of existing data for other herbal preparations involving same species; findings for one preparations cannot necessarily be extrapolated to other preparations involving same species • Some specialist journals do have reporting guidelines for describing herbal preparations tested, but not necessarily enforced; differences across journals • Clinical trialists, preclinical researchers, editors, authors, reviewers (and readers!) need reliable and consistent guidance on what information should be reported in clinical trials (and other experiments) involving herbal preparations

13. Objective: • To develop applications of existing CONSORT items to improve the reporting of RCTs of herbal medicine interventions

14. Methods (1) Participants Trialists, methodologists, pharmacologists, pharmacognosists, journal editors, CAM practitioners, Government, Industry, CONSORT members & others with expertise in herbal medicine International group: Canada, US, UK, Germany, India Modified Delphi technique Phase 1: Pre-meeting telephone calls (n = 16) • Mailed out readings and instructions • Individual phone calls - Applications of CONSORT items - New/additional items • Summarized results for presentation at consensus meeting

15. Methods (2) Phase 2: Consensus meeting • Toronto, Canada; June 28 & 29 2004 • N=14 + 2 RAs, chair, coordinator • Round 1: Pre-meeting revisions & new items presented and openly discussed • Evidence for and against each presented • Discussion continued until consensus was reached • Round 2: Results reviewed and discussed further until consensus was reached Phase 3: Post-meeting feedback • Results of consensus meeting mailed to participants • Item extensions (Short paper) • Meeting minutes • Edits and revisions incorporated • Wider CONSORT group offered edits • Explanation and elaboration document was completed

16. Results • New/additional items beyond CONSORT not needed • Elaboration of 9 CONSORT items to RCTs of herbal medicine interventions necessary • The elaboration of Item 4 (Description of the intervention tested) is particularly important

17. Item 4: Intervention Precise details of the interventions intended for each group and how and when they were actually administered. Where applicable, the description of a herbal intervention should include: A. Herbal medicinal product name B. Characteristics of the herbal product C. Dosage regimen and quantitative description D. Qualitative testing E. The rationale for the type of control/ placebo used F. A description of the practitioners (e.g., training and practice experience) that are a part of the intervention

18. Item 4: Intervention A. Herbal medicinal product name 1. The Latin binomial and common name(s) together with botanical authority and family 2. The proprietary product name (i.e. brand name) or the extract name (e.g., EGb-761) and the manufacturer of the product 3. Whether the product used is licensed/authorised in the country in which the trial/experiment was conducted

19. Item 4: Intervention B. Characteristics of the herbal product 1.The part(s) of plant contained in the product or extract. 2.The type of product used [e.g., raw (fresh or dry), extract] 3.The type and concentration of extraction solvent used (e.g., 80% ethanol) and the plant to plant extract ratio (drug:extract ratio; e.g. 2:1) 4.The method of authentication of raw material (i.e., how done and by whom) and the lot number of the raw material.

20. Item 4: Intervention C. Dosage regimen and quantitative description 1.The dosage of the product, the duration of the trial and how these were determined. 2.The quantity of all known herbal product constituents, both native and added per dosage unit form. 3. Whether the product was standardised and, if so, for which chemical component(s) of the product) and how (e.g., chemical processes, or biological/functional measures of activity) and quantity of active/marker constituents per dosage unit form. 3. Details of excipients.

21. Item 4: Intervention D. Qualitative testing 1. Product’s chemical fingerprint and methods used (equipment and chemical reference standards) and who performed it (e.g., the name of the laboratory used). If a voucher specimen (i.e., retention sample) was retained and if so, where it is deposited and reference number. 2. Description of special testing/purity testing (e.g., heavy metal or other contaminant testing). Which unwanted components were removed and how. E. The rationale for the type of control/ placebo used F. A description of the practitioners (e.g., training and practice experience) that are a part of the intervention

22. Other items 6 Outcomes: Clearly defined primary and secondary outcome measures and, when applicable, any methods used to enhance the quality of measurements (e.g., multiple observations, training of assessors). Outcome measures should reflect the intervention and indications tested considering, where applicable, underlying theories and concepts. 15 Baseline data: Baseline demographic and clinical characteristics of each group. Including, concomitant medication or NHP use, especially herbal medicinal product use. 20 Interpretation: Interpretation of results, taking into account study hypotheses, sources of potential bias or imprecision, and the dangers associated with multiplicity of analyses and outcomes. Interpretation of theresults in light of the product and dosage regimen used. 21 Generalisability: Generalizability (external validity) of trial results. Where possible, discuss how dose and dosage regimen used relates to what is used in self-care and/or practice. 22 Overall evidence: General interpretation of the results in the context of current evidence. Discussion of the trial results in relation to trials of other available products.

23. Broad consensus Anchored in established work (CONSORT) Endorsement CONSORT Group Dissemination Multiple peer-reviewed publications Exemplar RCTs Journal endorsement Instructions to authors Granting agencies Research societies and organizations Broad consensus Consensus method Lack of psychometric properties; list not intended to generate a score Not representative of all forms of herbal medicine?? May not be accepted by journals; specialist journals may prefer their own guidelines Discussion Strengths Weaknesses

24. Discussion • If used by authors and enforced by journal editors, the recommendations are likely to lead to improvement in the quality of reporting of trials involving herbal medicine interventions • CONSORT guidelines have led to improvement of reporting across time 1 • 58.5% of CONSORT items in 1994 • 67.8% in 1998 (p<0.001) Moher et al JAMA. 2001;285(15):1992-5 • Methodological quality items are more completely reported in trials published in CONSORT adopter journals VS non-adopters Devereaux et al. Contr Clin Trials 2002;23:380-8 • Recommendations apply equally to herbal medicine interventions assessed in other clinical research designs, and to preclinical experiments

25. Future Research • These guidelines are open to revision as: • More evidence becomes available • Comments accrue from the scientific public • Things we forgot! Eg chemovar • Periodic consensus meetings and publication of revisions • Reliability and validity analyses • Testing of influence on the literature

26. Acknowledgements • This study was funded in part by an operating grant from the Canadian Institutes of Health Research, Clinical Trials Divisions; Grant number: ATF-66679. • J Gagnier is supported by a post-graduate fellowship from the Canadian Institutes of Health Researchand the Natural Health Products Directorate • Auckland Medical Research Foundation and School of Pharmacy, University of Auckland for supporting J Barnes attendance at World Congress on Chinese Medicine

27. View over Karekare to Whatipu