Eisenberg et al. 2. Relevance of herbal and TCM products Roughly half of all approved prescription drugs are natural products, mostly from plants and microbial sources, their semi-synthetic derivatives or fully synthetic analogs [2]. Close to 70% of all cancer drugs originated from natural products 3, 4]. Therefore, the application of state-of-the-art technologies to the systematic evaluation of traditionally used plant based >E9 medicines(aka ethnobotanicals) remains a highly relevant yet scientifically challenging line of inquiry. 3. Epidemiology and market relevance of herbal and TCM products Herbal medicine use by the American public has increased dramatically over the past two decades. The percentage of US adults reporting the use of herbal(non-vitamin, non-mineral) products to treat or prevent disease increased from 2.5% in 1990 [5] to 12% in 1997[6]to 14% in 2000[7] to 19%o in 2002 [8] and 18% in 2007[9]. The estimated out-of-pocket expenditures for herbal therapies by the US adult population in 2007 was $14 8B. This is equivalent to approximately one-third of the total out-of-pocket spending on all prescription drugs(476B)that same year [10] A marketing analysis suggested that sales of TCM herbal products from China increased at an annual rate of 24% between 2004 and 2008[11]. In 2008, TCM herbal product sales accounted for an estimated 22% of Chinas overall healthcare product revenue and were estimated at a value of $26 billion US dollars [111 P9z 4. Rationale to build a prototy pe library based on challenges and lessons learned 4.1. Lessons learned from selected clinical trials In 2003, the NIH,'s National Center for Complementary and Alternative Medicine (NCCAM)warned that a lack of reproducibility, quality control and dosage schedules involving natural products might lead to methodologically questionable and/or negative clinical studies, thereby diminishing opportunities for further investigations of thnobotanicals [12] By way of example, in 2004 a randomized trial was conducted to test the clinical effectiveness of an eight herb Chinese formula, sold under the product name"PC-SPES, in subjects with advanced prostate cancer [13]. As documented in the medical literature, this complex herbal mixture was found to be clinically superior to the standard, high dose estrogen salvage protocol in terms of overall reductions in PSA levels and time to progression of disease for 90 randomized study subjects. However, random testing of the herbal mixture revealed it had been adulterated with small quantities of synthetic estrogen and Coumadin [ 13]. The authors concluded that the true efficacy of this, and other, herbal mixtures will remain uncertain until the quality, consistency and purity of the natural 9 products under evaluation can be ensured [13].A of the medical literature in 2005 documented that most publications involving the assessment of herbal therapies in clinical trials involved no independent verification of the herbal contents under evaluation [14] The authors of the PC-SPES study also commented on the fact that the levels of estrogen identified in the commercial PC-SPES products were far too low to have explained the apparent clinical superiority of the PC-SPES therapy as compared with the estrogen salvage protocol. As such, their comments could be interpreted to raise the possibility, albeit remote that specific components(i.e. chemical compounds) within the PC-SPES mixture, when Autho2. Relevance of herbal and TCM products Roughly half of all approved prescription drugs are natural products, mostly from plants and microbial sources, their semi-synthetic derivatives or fully synthetic analogs [2]. Close to 70% of all cancer drugs originated from natural products [3,4]. Therefore, the application of state-of-the-art technologies to the systematic evaluation of traditionally used plant based medicines (aka ethnobotanicals) remains a highly relevant yet scientifically challenging line of inquiry. 3. Epidemiology and market relevance of herbal and TCM products Herbal medicine use by the American public has increased dramatically over the past two decades. The percentage of US adults reporting the use of herbal (non-vitamin, non-mineral) products to treat or prevent disease increased from 2.5% in 1990 [5] to 12% in 1997 [6] to 14% in 2000 [7] to 19% in 2002 [8] and 18% in 2007 [9]. The estimated out-of-pocket expenditures for herbal therapies by the US adult population in 2007 was $14.8B. This is equivalent to approximately one-third of the total out-of-pocket spending on all prescription drugs ($47.6B) that same year [10]. A marketing analysis suggested that sales of TCM herbal products from China increased at an annual rate of 24% between 2004 and 2008 [11]. In 2008, TCM herbal product sales accounted for an estimated 22% of China’s overall healthcare product revenue and were estimated at a value of $26 billion US dollars [11]. 4. Rationale to build a prototype library based on challenges and lessons learned 4.1. Lessons learned from selected clinical trials In 2003, the NIH’s National Center for Complementary and Alternative Medicine (NCCAM) warned that a lack of reproducibility, quality control and dosage schedules involving natural products might lead to methodologically questionable and/or negative clinical studies, thereby diminishing opportunities for further investigations of ethnobotanicals [12]. By way of example, in 2004 a randomized trial was conducted to test the clinical effectiveness of an eight herb Chinese formula, sold under the product name “PC-SPES,” in subjects with advanced prostate cancer [13]. As documented in the medical literature, this complex herbal mixture was found to be clinically superior to the standard, high dose, estrogen salvage protocol in terms of overall reductions in PSA levels and time to progression of disease for 90 randomized study subjects. However, random testing of the herbal mixture revealed it had been adulterated with small quantities of synthetic estrogen and Coumadin [13]. The authors concluded that the true efficacy of this, and other, herbal mixtures will remain uncertain until the quality, consistency and purity of the natural products under evaluation can be ensured [13]. A review of the medical literature in 2005 documented that most publications involving the assessment of herbal therapies in clinical trials involved no independent verification of the herbal contents under evaluation [14]. The authors of the PC-SPES study also commented on the fact that the levels of estrogen identified in the commercial PC-SPES products were far too low to have explained the apparent clinical superiority of the PC-SPES therapy as compared with the estrogen salvage protocol. As such, their comments could be interpreted to raise the possibility, albeit remote, that specific components (i.e. chemical compounds) within the PC-SPES mixture, when Eisenberg et al. Page 3 Fitoterapia. Author manuscript; available in PMC 2012 January 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript