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Herbal research and global health: an ethical analysis Jon C Tilburt a & Ted J Kaptchuk b

Abstract Governments, international agencies and corporations are increasingly investing in traditional medicine research. Yet little literature addresses ethical challenges in this research. In this paper, we apply concepts in a comprehensive ethical framework for clinical research to international traditional research. We examine in detail three key, underappreciated dimensions of the ethical framework in which particularly difficult questions arise for international herbal medicine research: social value, scientific validity and favourable risk–benefit ratio. Significant challenges exist in determining shared concepts of social value, scientific validity and favourable risk–benefit ratio across international research collaborations. However, we argue that collaborative partnership, including democratic deliberation, offers the context and process by which many of the ethical challenges in international herbal medicine research can, and should be, resolved. By “cross-training” investigators, and investing in safety-monitoring infrastructure, the issues identified by this comprehensive framework can promote ethically sound international herbal medicine research that contributes to global health.

Bulletin of the World Health Organization 2008;86:594–599.

الرتجمة العربية لهذه الخالصة يف نهاية النص الكامل لهذه املقالة. .Une traduction en français de ce résumé figure à la fin de l’article. Al final del artículo se facilita una traducción al español

Introduction not faced in more conventional drug It is already widely used for immune Traditional herbal are development. boosting in AIDS. In vitro pharma- naturally occurring, -derived As attention and public funding cokinetic studies suggest potential substances with minimal or no industrial for international traditional herbal interference with vaccines, and animal processing that have been used to treat medicine research collaborations models show liver toxicity at very high illness within local or regional healing grows, more detailed analysis of ethical doses. There are no systemic side-effects practices. Traditional herbal medicines issues in this research is warranted. reported for humans in the literature. are getting significant attention in global Scant literature has addressed selected A few case series have shown mixed health debates. In , traditional issues such as informed consent and results. Local leaders are requesting the independent review related to tradi- government agency conduct a large, herbal medicine played a prominent 6,7 role in the strategy to contain tional herbal medicine research. Here randomized controlled trial (RCT) of and treat severe acute respiratory we apply a practical, comprehensive Africa Flower to test its efficacy as a syndrome (SARS).1 Eighty per cent of and widely accepted ethical framework novel adjunctive to slow pro- African populations use some form to international traditional herbal gression to AIDS. medicine research.8 We examine in de- of traditional herbal medicine,2,3 and tail difficult questions related to social the worldwide annual market for these Ethical framework value, scientific validity and favourable products approaches US$ 60 billion.2 Cases like these present challenging risk–benefit ratio. We conclude with Many hope traditional herbal medicine questions related to the role of traditional implications for future research in this research will play a critical role in herbal medicines in public health. area, focusing on the importance of global health. China, , Nigeria, In general, international research on collaborative partnership. the of America (USA) traditional herbal medicines should be and WHO have all made substantial subject to the same ethical requirements Case 9 research investments in traditional as all research related to human subjects. herbal medicines.2 Industry has also A government agency from a devel- An ethical framework previously invested millions of US dollars looking oped country is conducting an HIV- outlined by Emanuel et al. and revised for promising medicinal and treatment trial in Africa. A traditional for international research8 offers a useful novel chemical compounds.4,5 This is herbal medicine, Africa Flower, has starting point for thinking about the still a relatively modest investment been used for decades to treat wasting ethics of international traditional herbal compared to the overall pharmaceutical symptoms associated with HIV. Local medicine research. This framework industry; however, it raises interesting healers believe includes eight ethical requirements ethical questions, some of which are Africa Flower is an effective antiviral. for clinical research (Table 1).8

a Department of Clinical Bioethics, National Institutes of Health, Bethesda, MD, United States of America. b Osher Institute, Harvard Medical School, Boston, MA, USA. Correspondence to Jon C Tilburt (e-mail: [email protected]). doi:10.2471/BLT.07.042820 (Submitted: 2 April 2007 – Revised version received: 2 October 2007– Accepted: 25 October 2007 )

594 Bulletin of the World Health Organization | August 2008, 86 (8) Special theme – Ethics public health Jon C Tilburt & Ted J Kaptchuk Ethics and herbal medicine research

These ethical requirements are universal Table 1. A comprehensive framework for research ethics and comprehensive but must be adapted to the particular social context in which Ethical requirement Definition the research is implemented.8 Of these, fair subject selection, independent Collaborative Research leadership must include bilateral representation based review, informed consent, and respect partnership on mutual respect between equal partners with community advice. It includes a responsibility to invest in the scientific training and for enrolled subjects have been discussed capacity-building for ongoing research in a host country where such previously in the literature on the resources are not well developed. ethics of global health research and Social value Knowledge gained from the research should have the potential to raise few issues unique to international 8 lead to new generalizable knowledge or improvements in health. traditional herbal medicine research. Partners should specify in advance to whom benefits will accrue and However, social value, scientific validity, in what way. and favourable risk–benefit ratio raise Scientific validity Research should be designed to produce beneficial and generalizable specific challenges in international herbal knowledge. This includes designing research so that it can be medicine research that have not been feasibly implemented in the settings where it will be conducted. adequately discussed. Fair subject selection Subjects should be selected on the basis of scientific importance, not based on convenience, vulnerability or bias. Social value Favourable risk– The potential benefits of individual participation should outweigh the All research should hold the potential benefit ratio risks of participation. Benefits to the community or population being to achieve social value. Different entities studied should also be optimized. Compelling societal benefit can may view the social value of traditional justify risks to individuals in certain circumstances. medicine research differently. Public- Independent review To maintain the integrity of the research, bodies not tied to the health officials are often eager to define investigators must agree that the risks and potential benefits of the the safety and effectiveness of herbal research are justified. medicines for conditions such as Informed consent Investigators must obtain valid permission for study participation from .3 Conversely, harm can arise subjects in a manner that is sensitive to the cultural context in which with the unscrupulous use of herbs the study is conducted. such as Africa potato (various Hypoxis Respect for subjects Researchers should have a plan for how the research results will be species).7 While some claim that such disseminated; ensuring participants know their right to withdraw, and medicines have “stood the test of time”, monitoring the research for relevant adverse events. they nonetheless pose serious challenges to investigators and regulators from developed countries, in which standards While public-health entities may may want to use traditional herbal of proof are closely linked to proven be concerned with defining the risks medicine research to expand the in- efficacy in RCTs. Accordingly, there and benefits of herbal medicines al- fluence of their culture’s indigenous has been a serious investment in herbal ready in use, entrepreneurs and cor- herbal practices in the global health- medicine research by public-health porations hope herbal medicines may care market. For instance, Nigeria’s bodies in many countries. China yield immediate returns from herbal president recently established a national recently launched a safety research medicine sales, or yield clues to prom- committee on traditional medicine programme focusing on herbal medicine ising chemical compounds for future with the expressed desire to boost injections from traditional Chinese pharmaceutical development. They Nigeria’s market share of traditional medicine.10 South Africa recently test individual herbs, or their compo- medicine.14 In developed countries, included the need for investigating nents, analysed in state-of-the-art high- the “need” for this research may be to traditional medicines within its national throughput screening systems, hoping protect the public. drug policy.11 to isolate therapeutic The perceived need for the research In the USA, the National Center or biologically active functional com- may justifiably differ across countries, for Complementary and Alternative ponents. In 2006, Novartis reported but without some basic agreement on Medicine at the National Institutes of that it would invest over US$ 100 mil- the primary source of social value for Health spent approximately US$ 33 lion to investigate traditional medicine the research it may be difficult to judge million on herbal medicines in fiscal in Shanghai alone.4,5 its ultimate impact. In the Africa Flower year 2005; in 2004 the National Can- Nongovernmental organizations case above, before agreements to study cer Institute committed nearly US$ 89 may be primarily interested in preserv- a herbal medicine are decided, partners million to studying a range of tradi- ing indigenous medical knowledge. must fully discuss potential differ- tional .12 While this scale of One such organization, the Associa- ences about the perceived “need” for investment pales in comparison to the tion for the Promotion of Traditional the research through public forums or total research and development ex- Medicine (PROMETRA), based in structured debates. Based on these frank penses of the pharmaceutical industry, Dakar, Senegal, is “dedicated to preserv- discussions, partners can assess whether it nevertheless reflects genuine public, ing and restoring African traditional the social values of partner countries industry and governmental interest in medicine and indigenous science”.13 are sufficiently compatible to warrant a this area. Governments in developing countries research partnership.

Bulletin of the World Health Organization | August 2008, 86 (8) 595 Special theme – Ethics and public health Ethics and herbal medicine research Jon C Tilburt & Ted J Kaptchuk Scientific validity difficult to generalize the results from Valid outcome measures Part of ensuring the social value of a formal, structured and highly moni- International herbal medicine research research includes devising and tored trial to what will happen in the must use outcome measures that ac- implementing sound science. Although widespread dissemination of the herbal curately capture the effects conferred international collaborative research on medicine. Nevertheless, herbal medi- by herbal medicines. However, con- herbal medicine is no exception, cine research must endeavour to achieve structs such as “physical functioning” discussing scientific validity as an a balance between internal and external or “psychological well-being” measured ethical requirement raises some specific validity. by the SF-36 quality of life instrument challenges, including the meaning of make little sense within the terminol- Inclusion and exclusion criteria 20 scientific validity, establishing inclusion ogy and ideas of TCM. Therefore to and exclusion criteria, using appropriate To ensure that research results are ex- accurately measure a TCM ’s effects outcome measures, and determining ternally valid, the inclusion and exclu- on quality of life, some investigators appropriate study designs. sion criteria for research participation have constructed and validated ana- should fit with existing diagnostic cat- loguous measures that more faithfully Balancing internal and external egories in the target population speci- detect the effects of TCM interven- validity fied by the research question. However, tions that make sense within that heal- ing tradition.20,21 Ideally, when new Building a valid basis for knowledge in conceptualizations of health and illness measures are introduced, they should herbal medicine will require balancing can vary across medical systems and overlap with existing outcome mea- two aspects of scientific validity: internal populations, making agreement on sures, so that the research can ade- and external validity.15 Internal validity valid inclusion and exclusion criteria quately contribute to the existing body means the research must reliably test for international herbal medicine re- of knowledge. hypothesized relationships between an search collaborations more difficult to achieve. intervention and an outcome under Determining research design controlled conditions. Internally valid During the SARS epidemic, tradi- research will typically try to answer a tional Chinese medicine (TCM) prac- While it is generally agreed that all focused research question that is salient titioners involved in the care of SARS human subjects research must maintain within the vocabulary and methods of patients characterized patients based valid study designs, questions arise the scientific community at the time on nosological categories derived from about the characteristics of a valid the research is conducted. External TCM including “deficiency of chi and research design. Two extreme positions validity refers to the applicability yin” as well as “stagnation of pathogenic are often defended. At one extreme, 17 some researchers trained in biomedical of the research results to a target phlegm”. Designing clinical trials us- methods of clinical investigation argue population outside the experimental ing these kinds of TCM categories as that the only valid source of knowledge conditions of the research study. External inclusion criteria would require signifi- regarding clinical efficacy must come validity must always be weighed against cant additional effort and biomedical from one type of research design, the the need for rigorous internally valid flexibility to implement. If one wanted randomized double blind, placebo- research. to test whether TCM works for popula- controlled trial. They argue that any This tension between internal and tions in south-east Asia affected by a deviations from this gold standard of external validity can be illustrated by a SARS-like illness, adapting the science scientific validity amount to worthless recent herbal medicine trial of Echina- to include traditional diagnostic cat- science. cea angustifolia egories may be critical for its ultimate for prevention At the other extreme, critics of 16 external validity. of parainfluenza virus infection. The biomedical research conducted on tra- If American researchers want to study was conducted under rigorous ditional medicines charge that attempts test a herb’s effects on heart failure, they experimental conditions, but many to evaluate traditional therapies with herbalists pointed out that study condi- might use the New York Heart Associa- biomedical methodologies may fail to tions did not sufficiently reflect how tion classification as part of the inclu- generate true knowledge, since that these medicines are actually used. Null sion/exclusion criteria. However, this knowledge itself depends on a scientific treatment trial results like these prompt classification makes little sense from a vocabulary that only makes sense from questions about the external validity TCM perspective, in which heart fail- within the concepts of biomedicine.22–24 (i.e. value and meaning) of the research. ure may be viewed primarily as either They worry that “standard notions of Was the herbal medicine truly ineffec- a heart yang chi deficiency or a kidney ... experimental design criteria repre- 18 tive, or did the experiment not reflect yang deficiency. TCM practitioners sent an imperialistic ‘western’ mode of the herb’s use in “real-world” practice? may prefer to categorize patients based thinking”.22,24 In herbal medicine there are often on pulses, tongue examination, and Research on herbal medicines huge variations in the way in which the other elements of traditional diagnosis. should typically employ experimental medicines are used in herbalist practice, Investigators have simultaneously used research designs such as the RCT. Even including herb source, preparation, both biomedical entry criteria and if research tools (including the RCT) dose and indication. Because tradi- stratified for TCM diagnosis.19 Such an are imperfect,25 they are thus far the tional herbal medicine practitioners approach is scientifically ideal because best methods we have for furthering may be unregulated and their products of its ability to maximize the external our knowledge.9,15 Consider how RCT lacking in , it may be validity of results. designs could be implemented in TCM,

596 Bulletin of the World Health Organization | August 2008, 86 (8) Special theme – Ethics public health Jon C Tilburt & Ted J Kaptchuk Ethics and herbal medicine research in which treatments are individual- sources with their own variability in agreed-upon standards of favourable ized to patients, often incorporating species, growing conditions and bio- risk–benefit ratio more difficult. In several, or even dozens, of herbs in a logically active constituents. They often order for international collaborative customized preparation. Despite these come into use by a process of trial and herbal medicine research to achieve its complexities, investigators have suc- error, or over centuries. Accordingly, in objectives, it will be important to es- cessfully adapted double-blind RCT clinical herbal medicine research there tablish standards of evidence for dem- designs to complex individually tai- is rarely a strong preclinical basis for onstration of safety before conducting lored Chinese herbs. Bensoussan et al. dosing, and there are significant loom- large-scale clinical trials evaluating the conducted a three-arm trial in which ing questions about product purity, efficacy of herbal medicines. they tested the comparative clinical ef- quality, chemical stability and active ficacy of standard complex herbal medi- constituents at the time herbal medi- Improving science through cines, customized therapy and placebo.26 cine trials are proposed.27,28 collaborative partnership Standard and customized therapy were Initiating large-scale research trials How can international collaborative comparably beneficial as compared to in such circumstances raises questions herbal medicine trials achieve the placebo. In other instances, cluster about whether the risks and benefits of ethical requirements outlined above? RCTs can allow for practitioner vari- research participation can be accurately Collaborative partnership, the first ability, while still rigorously testing the ascertained. Those reviewing protocols requirement for international research efficacy of a therapeutic approach. In should factor in the uncertainty as- ethics, provides both the rationale and cross-cultural settings, researchers can- sociated with product variability in the context for achieving appropriate not merely adopt alternative designs determining whether a herbal medicine application of the other ethical require- in an ad hoc manner, but must reflect trial has a favourable risk–benefit ratio. ments. Partners in these collaborations on and refine their research question, However, protocol reviewers (i.e. insti- must share vocabulary for all the re- and find a design that best answers the tutional review boards) should not pre- quirements, especially for social value, research question within the given cul- sume that because they are personally scientific validity, and favourable risk– tural context. unfamiliar with a herbal preparation benefit ratio. How can agreed-upon In recent years, growing attention that there is no credible or valuable language be achieved? As illustrated background evidence regarding safety has been paid to a group of additional here, these challenges are significant. In and potential efficacy. While research- important ethical issues surrounding the case presented earlier, investigators ers should provide such information publication bias, financial conflicts of should have reservations about imple- in protocol materials, reviewers must interest, and clinical trial registries. In menting a large-scale clinical trial for remain aware of the role their own lack the arena of traditional herbal medi- Africa Flower. Nevertheless, the local of familiarity may play in their ultimate cine, these same issues apply, and when interest in this substance may be valid judgements of risks and benefits of the cross-cultural differences exist in the and deserve some additional prelimi- research. definitions of valid science, as is the case nary investigation. Collaborative part- Researchers increasingly agree that in traditional herbal medicine research, nership displays a commitment by all these questions compound. For instance, it is important to establish a rational basis for dosing and standardization of parties in international research agree- until recently, there was a tendency to ments to work together for common see only positive studies published in biologically active compounds before conducting large-scale treatment tri- language and goals. China. It is, therefore, critically impor- als.29,30 These efforts can improve inves- To achieve collaborative partner- tant to the long-term scientific cred- tigators’ ability to assess the risks and ship, parties can engage in structured ibility of international traditional herbal benefits of participation in large-scale methods of democratic deliberation to medicine research that, at the outset, herbal medicine trials. Likewise, more devise shared language and concepts for partners agree about the standards rigorous monitoring of adverse events research. These methods have been used of scientific conduct, the disclosure of and standardized reporting of research to bring different parties together in a financial relationships, registration of results for both safety and efficacy data safe and collegial process of decision- 34 clinical trials, and adequate reporting will improve long-term efforts to en- making. Over time, collaborations of trial results. hance risk–benefit ratio determination could “cross-train” basic and clinical 31 investigators to more fully appreciate the Favourable risk–benefit ratio for trial participation. Cultural factors also may influence concepts and practices of the traditional In international herbal medicine re- judgements of the risks and benefits herbal medicine traditions, and develop- search, several practical challenges arise in herbal medicine research. For in- ing host countries would need to de- in making accurate risk–benefit de- stance, a cultural familiarity with many velop the basic literacy, knowledge and terminations. Typically, in American traditional Chinese herbal medicines skills among traditional medicine prac- pharmaceutical development, a step- in China may promote a familiarity titioners so that they see the value of wise process of drug testing occurs – a bias, accepting a widespread cultural rigorous clinical research.2 With a sus- compound is isolated, tested in tissue assumption of safety, based on the his- tained investment like this, it will be- cultures and animals, and then investi- torical use of herbal medicines.32 There come increasingly possible to conduct gated in phase 1, 2 and 3 clinical trials. may also be a cultural difference in sound international scientific investiga- However, herbal medicines are already emphasis placed on standardized ad- tion on traditional herbal medicine. in widespread use, are often used in verse events reporting in China.33 These Furthermore, sustainable collaborative combination, and are drawn from plant cultural differences make achieving research partnerships would benefit

Bulletin of the World Health Organization | August 2008, 86 (8) 597 Special theme – Ethics and public health Ethics and herbal medicine research Jon C Tilburt & Ted J Kaptchuk from robust and independent adverse- partnership that implements sound Funding: TJK is a consultant for Kan event reporting systems for herbal research designs. So envisioned, inter- Herbal Company, Scotts Valley, CA, medicines so that the risk–benefit ratio national herbal medicine research can USA. Partial funding for TJK was pro- for herbal medicine research can be contribute to global health. ■ vided by the National Center for Com- more clearly defined. plementary and Ethical challenges in international Acknowledgements at the National Institutes of Health, traditional herbal medicine call for a Franklin G Miller and Jack Killen gen- Bethesda, MD, USA. comprehensive framework. Addressing erously read and offered helpful sugges- these challenges requires collaborative tions on earlier versions of this paper. Competing interests: None declared.

Résumé Recherche en phytothérapie et santé dans le monde : analyse éthique Les gouvernements, les agences internationales et les entreprises et le rapport risque/bénéfice favorable applicables à l’ensemble investissent de plus en plus dans la recherche en phytothérapie de la recherche en collaboration internationale se heurte à des traditionnelle. Cependant, les difficultés éthiques de cette difficultés majeures. Nous affirmons néanmoins que le partenariat recherche sont peu abordées dans la littérature. Dans cet collaboratif, et notamment la délibération démocratique, offre article, nous appliquons les concepts d’un cadre éthique le contexte et le processus pouvant et devant permettre de complet à la recherche clinique en phytothérapie traditionnelle résoudre beaucoup des problèmes éthiques rencontrés dans internationale. Nous examinons en détail trois dimensions sous- la recherche internationale en phytothérapie. Moyennant une estimées et essentielles du cadre éthique, dans lesquelles se « formation croisée » des chercheurs et des investissements posent des problèmes particulièrement difficiles pour la recherche en infrastructures de surveillance de l’innocuité, l’identification internationale en phytothérapie : la valeur sociale, la validité des problèmes par ce cadre complet favorisera une recherche scientifique et le ratio risque/bénéfice favorable. La définition de en phytothérapie internationale valable sur le plan éthique et concepts partagés pour la valeur sociale, la validité scientifique contribuera à la santé dans le monde.

Resumen Investigación fitoterapéutica y salud mundial: análisis ético Gobiernos, organismos internacionales y empresas están valor social, validez científica y relación riesgo-beneficio favorable invirtiendo cada vez más en la investigación de medicamentos en las investigaciones internacionales en colaboración entraña herbarios tradicionales. Sin embargo, son escasas las retos importantes. Sin embargo, sostenemos que hay fórmulas publicaciones que abordan los problemas éticos asociados a de colaboración, en particular la deliberación democrática, que esas investigaciones. En este artículo aplicamos los conceptos brindan un contexto y unos procedimientos mediante los que manejados en un marco ético amplio de regulación de las se pueden, y se deben, resolver muchos de los dilemas éticos investigaciones clínicas a las actividades internacionales asociados a las investigaciones internacionales en materia de de investigación de medicamentos herbarios tradicionales. medicina herbaria. Formando de manera interdisciplinaria a los Examinamos en detalle tres dimensiones clave pero subestimadas investigadores e invirtiendo en infraestructuras de vigilancia de del marco ético en las que se plantean cuestiones particularmente la seguridad, las cuestiones identificadas mediante este marco difíciles para la investigación internacional de esos medicamentos: integral pueden fomentar la realización de investigaciones valor social, validez científica y relación riesgo-beneficio. El internacionales de medicamentos herbarios éticamente válidas proceso de consenso en torno a lo que deba entenderse por que contribuyan a la salud mundial.

ملخص بحوث طب األعشاب، والصحة يف العامل: تحليل للجوانب األخالقية يتزايد إقبال الحكومات والوكاالت والرشكات الدولية عىل االستثامر يف بحوث العلمية، والنسبة بني املخاطر واملنافع يف جميع مستويات التعاون البحثي طب األعشاب. غري أن القليل من الدراسات املنشورة تتصدى للتحديات الدويل. غري أن الباحثني يرون أن الرشاكة التعاونية، مبا يف ذلك املشاورات التي األخالقية يف هذه البحوث. ويف هذه الورقة يطبق الباحثون بعض املفاهيم، ُتجرى بطريقة دميقراطية، توفر السياق والخطوات التي ميكن، بل ينبغي، أن يف إطار عمل أخالقي شامل للبحوث الرسيرية، عىل بعض البحوث الدولية ُحلمن يخاللهام العديد من التحديات األخالقية يف البحوث الدولية يف مجال يف مجال طب األعشاب التقليدي. ويدرس الباحثون بالتفصيل ثالثة أبعاد طب األعشاب. وميكن للقضايا التي يحددها هذا اإلطار الشامل للعمل، أن رئيسية لإلطار األخالقي ال تلقى ما تستحقه من التقدير، والذي ُتطرح فيه تعزز البحوث الدولية السليمة أخالقياًيف مجال طب األعشاب، والتي تسهم أسئلة صعبة تدور يف مجال البحوث الدولية لطب األعشاب، وهي: القيمة يف تعزيز الصحة يف العامل، وذلك عن طريق التدريب املتعدد التخصصات االجتامعية، واملوثوقية العلمية، والنسبة بني املخاطر واملنافع. وتوجد للباحثني، واالستثامر يف البنية التحتية لرصد السالمة. تحديات مهمة يف تحديد املفاهيم املشرتكة للقيمة االجتامعية، واملوثوقية

598 Bulletin of the World Health Organization | August 2008, 86 (8) Special theme – Ethics public health Jon C Tilburt & Ted J Kaptchuk Ethics and herbal medicine research

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