India-United States Dialogue on Traditional Medicine: Toward Collaborative Research and Generation of an Evidence Base

Therapies originating from traditional medical systems are widely used by patients in both India and the United States. The first India-US Workshop on Traditional Medicine was held in New Delhi, India, on March 3 and 4, 2016, as a collaboration between the Ministry of Ayurveda, Yoga and Naturopathy, Unani, Siddha, and Homoeopathy (AYUSH) of the Government of India, the US National Cancer Institute (NCI), National Institutes of Health, and the Office of Global Affairs, US Department of Health and Human Services. It was attended by Indian and US policymakers, scientists, academics, and medical practitioners from various disciplines. The workshop provided an opportunity to open a dialogue between AYUSH and NCI to identify promising research results and potential topics for Indo-US collaboration. Recommendations that emerged from the workshop underlined the importance of applying rational and scientific approaches for drug development; standardizing traditional medicine products and procedures to ensure reliability and reproducibility; promotion of collaboration between Indian traditional medicine practitioners and researchers and US researchers; greater integration of evidence-based traditional medicine practices with mainstream medical practices in India; and development of training programs between AYUSH and NCI to facilitate crosstraining. Several positive developments took place after the thought-provoking deliberations.


INTRODUCTION
Traditional medicine (TM) is defined by WHO as "the sum total of the knowledge, skills and practices on the basis of the theories, beliefs and experiences indigenous to different cultures, whether explicable or not, used in the maintenance of health, as well as in the prevention, diagnosis, improvement or treatment of physical and mental illnesses." 1 Typically, TM is one of the main sources of health care in a country when one or more of the following conditions apply: strong cultural and historical influences, lack of available alternate forms of medicine, or as complementary therapy in addition to other forms of medicine.
India has 15 agroclimatic zones, 47,000 plant species, and 15,000 medicinal plants. This includes approximately 7,000 plants used in Ayurveda, 700 in Unani, 600 in Siddha, and 30 in modern medicine. This makes India one among 12 mega-biodiverse countries of the world. 2 In rural India, an estimated 65% of the population uses TM to help meet primary health care needs. 3 The Ministry of Ayurveda, Yoga and Naturopathy, Unani, Siddha, and Homoeopathy (AYUSH) of the Government of India was formed on November 9, 2014, by elevation of the Department of AYUSH, previously under the Ministry of Health and Family Welfare. 4 The Ministry of AYUSH aims to achieve the following: • Upgrade the educational standards in Indian Systems of Medicines and Homoeopathy colleges in the country, • Strengthen existing research institutions and ensure a time-bound research program on identified diseases for which these systems have an effective treatment, • Draw up schemes for promotion, cultivation, and regeneration of medicinal plants used in these systems, and • Evolve pharmacopeial standards for Indian Systems of Medicine and Homoeopathy drugs. 5 As part of the 12th Five-Year Plan (2012 to 2017), the Government of India launched the National AYUSH Mission, which envisages better access to AYUSH services through an increase in the number of AYUSH hospitals and dispensaries; mainstreaming of AYUSH through colocation of AYUSH facilities at primary health centers, community health centers, and district hospitals; and ensuring availability of AYUSH drugs and trained manpower. The plan also aims to improve the quality of AYUSH education through enhancement of the number of upgraded educational institutions, sustained availability of quality raw materials, and promoting medicinal plant conservation. 6 Of the three pharmacopeia committees for Ayurvedic, Siddha, and Unani drugs, the Pharmacopoeial Laboratory for Indian Medicines, Ghaziabad, has thus far published standards on 1,082 single drugs and 302 compound formulations. 7 The Ministry of AYUSH has also set up a research portal, managed by the In the United States, there is currently no standardized, national system for credentialing complementary health practitioners, and the credentials vary significantly from state to state and discipline to discipline. 16

STRENGTH OF AYUSH AND PROMISING AYUSH INTERVENTIONS FOR CANCER AND OTHER AREAS (PRESENTATIONS BY AYUSH SCIENTISTS)
The main thrust of this session was that AYUSH interventions/therapies have the potential to be used for regression of the disease process in cancer, managing its symptoms and complications, reducing the adverse effects from chemotherapeutic drugs, improving quality of life, increasing the survival period, and preventing recurrences and complications.
Chitra Mandal, PhD (Indian Institute of Chemical Biology, Kolkata), discussed a new molecule, CM-5, a carbazole alkaloid derived from the plant Murraya koenigii (Rutaceae), commonly known as curry leaf or kari patta, which has shown tumoricidal activity and also increased the efficacy of known cancer drugs in an animal model of various types of cancers at doses that did not cause serious systemic toxicity. CM-5 has also been shown to exhibit antiproliferative activity against several pancreatic cancer cells through apoptosis. 20 Similarly, a presentation by Subhash Padhye, PhD (Interdisciplinary Science and Technology Research Academy, Pune), demonstrated the potential anticancer therapeutic effects of a Unani intervention, black cumin seeds (Nigella sativa). The major active component of black cumin is thymoquinone, which demonstrates cytotoxic activity against pancreatic cancer cell lines by targeting the prolactin receptor.

RESEARCH PRESENTATIONS ON ALTERNATE SYSTEMS OF MEDICINE AND CANCER (PRESENTATIONS BY US SCIENTISTS)
This session provided examples of relevant US research projects and programs. Nagi Kumar, PhD, RD, Director, Cancer Chemoprevention, Moffitt Cancer Center, presented on chemoprevention and treatment of cancers with botanicals. She provided a detailed description of the process of drug development with reference to botanicals and discussed current challenges for targeted therapies in cancer, as well as the advantage of a multitargeted approach through botanicals. Limitations of the present biomarker-based approaches were also described, along with ways to overcome these limitations to facilitate botanical drug development.
Hasan Mukhtar, PhD, Helfaer Professor of Cancer Research, Director and Vice Chair for Research, Department of Dermatology, Wisconsin Medical Sciences Center, presented on natural products for cancer chemoprevention on the basis of lessons learned from animal experiments. Studies exploring potentially effective approaches for cancer control in humans were discussed. Encouraging findings from these prevention studies indicate the need for additional investigations of these and other natural products.
Guido Pauli, Pharm D, PhD, Professor and University Scholar at the University of Illinois at Chicago College of Pharmacy, presented on advancing the holistic approach to traditional plantbased medicine. He elaborated on the need to study natural products both qualitatively and quantitatively, and presented approaches for a more holistic analysis that captures the complex constitution of natural health products. Although marker compounds for natural products are used widely and globally, they should be thoroughly investigated and defined with caution. Validation methodology for chemotaxonomic and bioactive markers as well as potential leads for active pharmaceutical ingredients should be congruent.

GROUP DISCUSSION
Day 2 of the workshop began with discussions to identify research areas for Indo-US collaboration and to summarize the meeting outcomes. The workshop attendees were divided into three discussion groups: (1) Natural Products Research; (2) AYUSH Systems of Medicine in Cancer: What Holds Promise; and (3) Generating Evidence Toward Market Access for AYUSH Products and Practices.

Natural Products Research (Group 1)
The natural products research group discussed research methods, training needs, prerequisites for material transfer agreements with US NCI and Indian perspectives, intellectual property rights, and National Biodiversity Authority perspectives on benefit sharing and commercialization.
Several recommendations emerged from these discussions: • The need to add capacity for conducting research in natural products, including both single herbs and mixtures. Suggestions included building a central repository for cell lines, extracts, and fractions, as well as developing infrastructure for translation of validated research into clinical practice, including incubation of start-up companies.
• The need for harmonization of pharmacopeias from India and Western nations, including the United States. Important for such harmonization is the creation of a centralized laboratory for analytical methodology devoted to standardized quality control for Ayurvedic preparations. Such a facility would lead to the development of standard operating procedures (SOPs) for herbal and herbomineral preparations.
• The proposed enhancement of quality control and standardization in Ayurvedic preparations would better ensure the reproducibility of results among disparate laboratories to increase transferability between institutes and countries. To support such reproducibility studies, the group recommended that the Ministry of AYUSH encourage multicenter clinical studies on interventions for the most prevalent cancers in India and the United States. These studies should use a standard format for data collection, analyses, and management. Open dissemination of the results of such clinical trials and evaluation of their power and reproducibility are critical.
• Additional recommendations included focusing on the strengths of traditional medical systems such as rasayanas (and similar medicinal preparations) and the development of specialized expertise in intellectual property rights.

AYUSH Systems of Medicine in Cancer: What Holds Promise? (Group 2)
The overall goal of this group was to identify research gaps and ultimately develop steps for generating evidence and moving research to practice. The group discussed research methods, training needs, and next steps. The focus was on epidemiology studies, palliative care, and support studies. The discussion led to the following recommendations: • Evidence to translate research to practice should be obtained in a culture of collaboration, ensuring communication and cooperation among all stakeholders, including AYUSH, extramural scientists, clinicians, and pharmaceutical/biotechnology companies. AYUSH activities should be well integrated, involving both basic scientists and clinical teams.
• Basic research is needed to generate robust supporting data for claims regarding the integrity, safety, and efficacy of botanicals that are well founded (eg, effects on immunity), to inform the development and implementation of clinical trials.
• There is a critical need to develop guidelines and standard operating procedures to ensure product integrity (standardization, stability), including a clear understanding of biology, molecular targets, safety, and indications for use of AYUSH products.
• Clinical trials should be performed with scientific rigor and include safety and clinical efficacy studies. Focus areas should include adjuvant therapy and remission therapy by AYUSH modalities, benefits from such approaches in the form of personalized medicine, and improvement in quality of life.
• Mechanisms should be established that encourage the articulation of results of TM observations in scientific meetings and their publication in peer-reviewed journals.
• With regard to the training and education of the next generation of TM practitioners, the group felt that joint Indo-US training programs would be mutually beneficial. One particular recommendation was the joint development of protocols for clinical and basic research. Such protocols should consider quantitative clinical parameters.
• Finally, the formation of US-India activity groups was recommended to continue discussions of relevant topics.

Generating Evidence Toward Market Access for AYUSH Products and Practices (Group 3)
The overall goals of this group were to identify gaps, define the key role of research, discuss approaches to implementing validation studies, consider the role of rigorous clinical trials, and identify areas for collaboration that would ultimately lead to generating sufficient evidence to move research results into clinical practice. Recommendations from this group included the following: • Recognize the need to advance basic sciences in AYUSH by establishing collaborations among basic, clinical, and population science research teams as well as the private sector and industry.
• Establish guidelines and standards for product integrity in terms of biology, targets, and rigor/reproducibility, including developing SOPs for product development, validation, batch-to-batch consistency, preclinical models, and clinical trials.
• Build centralized Good Manufacturing Practice laboratories, using established manufacturing practices for product development and create a hub for making this information, including cost of production of products, available to all users.
• Establish a regulatory structure to address consistency in standards of research conduct and compliance.
• Articulate and publish findings of studies conducted using rigorous scientific methodology.
• Create cross-disciplinary exchange and scholarships, including a platform for joint India-US conferences and/or symposia, providing training opportunities across and within disciplines.

RECENT DEVELOPMENTS
After the workshop, the participating agencies agreed to adopt a multidisciplinary approach for moving ahead in the intersection of Indian collaborations. These progressive developments will help take forward the shared commitments of the two countries in the field of TM.
In conclusion, the workshop served as an important initial engagement for the Ministry of AYUSH, HHS-Office of Global Affairs, and NCI to discuss cooperative activities in areas including research training and research programs. These discussions highlighted the opportunities to develop rigorous scientific portfolios and collaboration, while integrating existing knowledge, clinical best practices, and considering regulatory issues that govern the process of bringing scientific results to the benefit of public health.
The workshop provided a comprehensive understanding of existing gaps, such as inclusion of rational and scientific approaches for drug development; policies and procedures that can help develop milestones/expected outcomes; promotion of collaborative research; implementation of regulatory structures to ensure product reproducibility; and development of procedures and principles for product validation. The workshop also provided the opportunity for NCI and AYUSH researchers to begin engagement that continues as agreements and priorities are formalized.
Several important recommendations emerged from the workshop, such as the need for basic sciences in deepening the understanding of TM; creation of cross discipline exchange/scholarships; development of centers of excellence; centralized laboratories; a platform for joint India-U.S. conferences and symposia to share and acquire knowledge; a hub of standardized information; regulatory structure and compliance; and development of Good Manufacturing Practice facilities. It would seem highly beneficial to link together some of the well-established centers in India for basic, translational, and clinical research with joint projects. Such projects should emphasize product supply and encourage industries to participate in product development. Development of plant biotechnology was another area of interest. Implementing data and procedure optimization via development of SOPs and validation procedures was highly recommended. Development of training programs for TM scientists and medical practitioners, as well as crosstraining opportunities across all relevant disciplines, was also prominent among the recommendations.
The first bilateral workshop provided a strong foundation for AYUSH, NCI, and their partners to work together on implementing the recommendations for better development and promotion of the growth of traditional Indian medicine research, advancing its evidence-based practice, and defining its role in the care of patients with cancer in an integrated fashion with conventional biomedicine. A Centre for Integrative Oncology is in place to coordinate interactions on cancer-related research at the national and international levels.
One of the premium institutes of Ayurveda has been designated as a nodal institute for cancer research. Efforts are under way to formalize the collaboration between HHS and AYUSH to advance the research and regulatory capacity of TM.