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http://www.sciencemag.org/cgi/content/full/313/5785/301
SCIENCE AND GOVERNMENT:
Enhanced: Review for NCCAM Is Overdue
Donald M. Marcus1* and Arthur P. Grollman2
The U.S. National Institutes of Health (NIH) were created by Congress to conduct research on the causes and treatment of common diseases. In contrast, the National Center for Complementary and Alternative Medicine (NCCAM) was created by pressure from a few advocates in Congress (1-3). The NCCAM budget for 2005 was $123.1 million. At a time when NIH support of biomedical research is decreasing (4) and many excellent grant proposals are not being funded, NCCAM';s expenditure of funds deserves scrutiny.
History of OAM and NCCAM
NCCAM began as the Office of Alternative Medicine (OAM) in 1992 (1-3). It was created within the office of the NIH director with a budget of $2 million by a directive from the Senate Appropriations Committee. The driving force behind the directive was Senator Tom Harkin (D-IA), chairman of the Appropriations Committee, a long-time supporter of NIH research and advocate for alternative medicine.
In 1997, Senator Harkin proposed that OAM become an independent center with direct authority to appoint peer-review panels and to award grants. Despite opposition to this proposal from prominent scientists, including former presidential science adviser D. Allen Bromley and Nobel laureates Paul Berg and Jerome Friedman (5, 6), NCCAM was created in 1998 with an initial budget of $50 million. In response to Harkin';s complaints that alternative medicine specialists were excluded from previous review panels, the new NCCAM charter stipulated that 12 of the 18 members of the NCCAM Advisory Council "shall be selected from among the leading representatives of the health and scientific disciplines … in the area of complementary and alternative medicine. Nine of the members shall be practitioners licensed in one or more of the major systems with which the Center is involved" (7).
In 1999, Stephen Straus, a respected virologist and immunologist, and chief of the Laboratory of Clinical Investigation of the National Institute of Allergy and Infectious Diseases, was appointed director of NCCAM. He has stated frequently that alternative therapies can and should be evaluated by the same methodology used in clinical trials of conventional treatments (8). What kinds of studies has NCCAM funded?
CREDIT: PHOTOS.COM
Clinical Trials Funded by NCCAM
A major emphasis of NCCAM';s first 5-year strategic plan was to perform phase III clinical trials of popular herbal medicines and other supplements to inform the public about their efficacy (9). Accordingly, the fraction of funds allocated to clinical research by NCCAM has been high, ranging from 80% in fiscal 2000 to 68% in 2004, compared with ~33% by the rest of NIH. The results of clinical trials of St. John';s wort, echinacea, and saw palmetto have been published (10-12), and none of these herbal medicines was more effective than the placebo controls. Although Straus has commented that "he for one is satisfied that echinacea is not an effective cold remedy" (13), spokesmen for the herbal and nutraceutical industries predictably responded that the studies were flawed and that more research is needed. It appears doubtful that these negative trials will change the practices of many people who use herbal remedies, given their belief in the healing power of natural products and their distrust of physicians, scientists, and the pharmaceutical industry. When regular users of dietary supplements were asked, "If a government agency said that the dietary supplement is ineffective, what would you do?," 71% responded that they would keep using the supplement (14).
NCCAM';s strategic plan for 2005-09 (9) recognizes the lack of quality control of commercial herbal products, a problem that is a consequence of the Dietary Supplement Health and Education Act of 1994 (DSHEA), which markedly restricts the Food and Drug Administration';s (FDA';s) authority to regulate dietary supplements. As Berman and Straus stated (8), "Herbal medicines are plagued by contamination with heavy metals and filth, by adulteration with prescription drugs, wide divergence from labeled content, interference with the pharmacokinetics of life-saving drugs, and even some inherent toxicities," an assessment that is supported by many reviews (15, 16).
To improve the quality of natural products used in clinical trials, NCCAM recommended chromatographic analysis of extracts and of their putative active ingredients (17). However, the number and identity of the active ingredients of most herbal remedies are unknown, and chromatographic standardization would not ensure standardization of biological activity or stability. Moreover, because there are few regulations governing herbals manufacture, products bought by the public will differ from the research materials. We see little reason, therefore, for NCCAM to continue to finance expensive clinical trials of plant extracts (18).
Two clinical trials supported by NCCAM deserve comment. In collaboration with the National Heart, Lung, and Blood Institute, NCCAM is funding a 5-year $30 million trial of EDTA (ethylenediaminetetraacetic acid) chelation therapy for coronary artery disease (19). It is being carried out at more than 100 sites and involves over 2300 patients. The justification for this study is that many patients are receiving chelation therapy, although it is not approved by the FDA and off-label use for treating heart disease is currently illegal. The American Heart Association and other national medical organizations have issued statements concerning the lack of evidence for its benefit (20), and smaller controlled trials (21-24) have found chelation therapy to be ineffective. Will another negative trial modify the practice of individuals who choose to ignore existing negative evidence and risk legal sanctions?
Another clinical trial compares the use of the chemotherapeutic agent gemcitabine with the Gonzalez regimen in patients with stages II to IV pancreatic cancer (25). The beliefs that underlie this regimen are that cancer is caused by a deficiency of pancreatic proteolytic enzymes that would normally eliminate cancer cells and their toxic products, and that environmental toxins cause imbalances in the body that lead to cancer (26). Patients are treated with porcine pancreatic enzymes, coffee enemas twice daily, and nutritional supplementation that includes Papaya Plus, vitamins, minerals, "animal glandular products," and other products four times daily. Severe adverse effects have been associated with the Gonzalez regimen (26, 27).
Two important criteria used by scientific review groups to evaluate grant proposals are scientific plausibility and promising preliminary data. No evidence in peer-reviewed journals supports either the plausibility or the efficacy of chelation therapy or the Gonzalez protocol. We believe that funding these projects confers undeserved legitimacy on alternative practices and reflects poorly on the NIH review process.
Review Groups and Advisory Panels
Because of its charter, NCCAM review groups include individuals whose primary training is in alternative therapies, as well as representatives of the botanical industry. In terms of training and publications in medical and scientific journals, their scientific credentials are limited; also, some have potential conflicts of interest. Well-qualified scientists also serve on NCCAM review panels, but their influence is constrained by the narrow NCCAM agenda that emphasizes trials of alternative therapies.
Another problem is that a handful of individuals have been influential in shaping the agendas of OAM and NCCAM. Since the inception of OAM in 1992, those who have written policy papers (28) also have served on review panels and advisory groups and have received numerous grants for research and education.
Evaluation of NCCAM
Oversight of extramural programs is the responsibility of the advisory councils of institutes and centers. The extramural program of NCCAM has escaped critical evaluation because its charter requires a preponderance of proponents of alternative medicine on its council.
In 2002, the Institute of Medicine (IOM) was commissioned by NIH and the Agency for Healthcare Research and Quality (29) to "explore scientific, policy and practice questions that arise from the significant and increasing use of CAM [complementary and alternative medicine] therapies by the American public." One of three tasks assigned to the IOM Committee was to "Identify major scientific, policy and practice issues related to CAM research." Seven of the 17 committee members were CAM practitioners or directed CAM and integrative medicine centers. The IOM report identified problems in CAM research, such as the variable composition of herbal medicines and limited number of individuals with research training in the CAM community. Unfortunately, the IOM committee did not evaluate the quality of NCCAM-funded trials or the value of spending hundreds of millions of dollars on CAM research.
Conclusions
We believe that NCCAM funds proposals of dubious merit; its research agenda is shaped more by politics than by science; and it is structured by its charter in a manner that precludes an independent review of its performance. The central issue is not whether research into alternative therapies should be supported by NIH. In view of the popularity of alternative therapies, it is appropriate to evaluate the efficacy and safety of selected treatments. The issue is that the administration of research by NCCAM falls below the standards of other NIH institutes and that the evaluation of alternative therapies could be performed by mechanisms that are already in place at NIH. We do not question the qualifications or integrity of Stephen Straus and his staff. However, because of the constraints under which it operates, NCCAM is unable to implement a research agenda that addresses legitimate scientific opportunities or health-care needs (30). Applicants for NCCAM grants must follow the center';s guidelines that stipulate which therapies are eligible for study. In contrast, applicants to NIH institutes can propose any project that may provide new insights into human biology or the pathogenesis or treatment of disease.
Recommendations
We propose that the IOM appoint an independent panel of scientists to review NCCAM. The panel should evaluate the center';s unique charter as well as its research portfolio, and its members should not include NIH or NCCAM staff, NCCAM grantees, and other stakeholders. An independent review is likely to be strongly opposed by members of Congress whose beliefs led to the creation of NCCAM and the passage of the DSHEA. Therefore, scientists and professional organizations should communicate to Congress and to Elias Zerhouni, the director of NIH, their strong support for an external assessment of NCCAM.
References and Notes
J. H. Young, Bull. Hist. Med. 72, 279 (1998) [Medline].
E. Marshall, Science 265, [2000] (1994).
S. Budiansky, U.S. News World Rep., 17 July 1995, p. 48; (www.usnews.com/usnews/culture/articles/950717/archive_032434.htm).
J. Mervis, Science 311, 28 (2006).
G. Vogel, Science 278, 378 (1997).
J. Couzin, Science 282, 2175 (1998).
National Advisory Council for Complementary and Alternative Medicine (NACCAM) (http://nccam.nih.gov/about/advisory/naccam/charter.htm).
J. D. Berman, S. E. Straus, Annu. Rev. Med. 55, 239 (2004) [Medline].
"Expanding horizons of health care: Strategic plan 2005-2009" [National Center for Complementary and Alternative Medicine (NCCAM), U.S. Department of Health and Human Services, National Institutes of Health, Bethesda, MD, 2005] [Summary/full text].
J. S. Markowitz et al., JAMA 290,1500 (2003) [Medline].
R. B. Turner et al., N. Engl. J. Med. 353, 341 (2005) [Medline].
S. Bent et al., N. Engl. J. Med. 354, 557 (2006) [Medline].
G. Kolata, New York Times, 28 July 2005.
R. J. Blendon, C. M. DesRoches, J. M. Benson, M. Brodie, D. E. Altman, Arch. Intern. Med. 161, 805 (2001) [Medline].
P. A. G. M. De Smet, Clin. Pharmacol. Ther. 76, 1 (2004) [Medline].
M. Elvin-Lewis, Adv. Food Nutr. Res. 50, 219 (2005) [Medline].
NCCAM, Policy announcement on the quality of natural products, 2003; (http://nccam.nih.gov/research/policies/bioactive.htm).
W. Sampson, N. Engl. J. Med. 353, 337 (2005)[Medline].
"NIH launches large clinical trial on EDTA chelation therapy for coronary artery disease," press release, 30 August 2002; (http://nccam.nih.gov/news/2002/chelation/pressrelease.htm).
"Questions and answers about chelation therapy," American Heart Association (www.americanheart.org/presenter.jhtml?identifier=3000843).
E. Ernst, Am. Heart J. 140,139 (2000) [Medline].
M. L. Knudtson et al., JAMA 287, 481 (2002) [Medline].
M. V. Villaruz, A. Dans, F. Tan, Cochrane Database Syst. Rev. 2002(4), CD002785(2002).
D. M. R. Seely, P. Wu, E. J. Mills, BMC Cardiovasc. Disord. 5, 32 (2005) [Medline].
Gemcitabine compared with pancreatic enzyme therapy plus specialized diet (Gonzalez regimen) in treating patients who have stage II, stage III, or stage IV pancreatic cancer (http://clinicaltrials.gov).
Metabolic therapy, American Cancer Society (www.cancer.org).
S. Green (www.quackwatch.org/01QuackeryRelatedTopics/Cancer/kg.html).
"Alternative medicine: Expanding medical horizons: A report to the National Institutes of Health on alternative medical systems and practices in the United States," Workshop on Alternative Medicine, Chantilly, VA, 14 to 16 September 1992 (Government Printing Office, Washington, DC, 1995).
Committee on the Use of Complementary and Alternative Medicine by the American Public, Complementary and Alternative Medicine in the United States (Institute of Medicine, The National Academies Press, Washington, DC, 2005), chap. 9. [publisher';s information]
E. Stokstad, Science 288, 1568 (2000).
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10.1126/science.1126978
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1Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
2Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.
*Author for correspondence. E-mail: dmarcus@bcm.tmc.edu
HyperNotes
Related Resources on the World Wide Web
Alternative Medicine
National Center for Complementary and Alternative Medicine (NCCAM)
Offers health information sorted by disease and treatment, as well as information about CAM-related research, clinical trials, and training.
MedlinePlus: Alternative Medicine
A comprehensive collection of Internet resources from the National Library of Medicine (NLM).
Mayo Clinic Complementary & Alternative Medicine Center
A collection of articles and resources, including a CAM primer, made available by the Mayo Foundation for Medical Education and Research.
The Alternative Medicine HomePage
A directory of resources including databases, mailing lists, and practitioners'; directories, maintained by medical librarian C. B. Wessel of the Health Libraries System, University of Pittsburgh.
Index of Alternative Therapies and Modalities
Offers an overview of a variety of complementary medical techniques; a project of the Harvard Medical School-InteliHealth Partnership.
WholeHealthMD
A Web-based resource for CAM information that includes news and perspectives, expert opinions, and a reference library.
Herbal Medicine and Dietary Supplements
Information Resource: About Herbs, Botanicals, and Other Products
Evidence-based information about herbs, botanicals, vitamins, and other supplements; from the Memorial Sloan-Kettering Cancer Center.
Botanical Dietary Supplements: Background Information
A fact sheet provided by the National Institutes of Health Office of Dietary Supplements.
MedlinePlus: Herbal Medicine
A collection of Internet resources from NLM.
HerbMed®
An evidence-based herbal database providing hyperlinked access to scientific research on herbs; a project of the Alternative Medicine Foundation.
NLM Directory of Herbs and Supplements
Entries include background information as well as details about dosing, safety and efficacy, and drug interations.
International Bibliographic Information on Dietary Supplements (IBIDS) Database
Provides access to bibliographic citations and abstracts from published, international, and scientific literature on dietary supplements, from the NIH Office of Dietary Supplements.
CAM Research and Clinical Trials
NCCAM Clinical Trials
Site includes a fact sheet, policies and guidelines for researchers, a listing of all NCCAM trials, and published results.
ClinicalTrials.gov
A database of federally and privately supported clinical research that includes listings of trials involving complementary therapies such as herbal medicine and acupuncture.
Allied and Complementary Medicine Database (AMED)
A bibliographic database containing primarily European references from journals on alternative and complementary medicine going back to 1985; produced by the Health Care Information Service of the British Library.
The Arthritis and Complementary Medicine Database (ARCAM) and the Complementary and Alternative Medicine and Pain Database (CAMPAIN)
Compiled from regular, comprehensive electronic and hand searches of scientific literature sources worldwide; maintained by the University of Maryland Center for Integrative Medicine.
CAM on PubMed
A searchable subset of citations of journal articles related to complementary and alternative medicine.
Comprehensive and Alternative Medicine Specialist Library
Part of the UK';s National Library for Health, the collection aims to provide access to the best available evidence in the field of CAM.
Further Reading
Complementary and Alternative Medicine in the United States
A 2005 report from the National Academies Institute of Medicine.
"Bastions of Tradition Adapt to Alternative Medicine"
A News Focus by E. Marshall in the 2 June 2002 issue of Science.
"Stephen Straus';s Impossible Job"
A News Focus by E. Stokstad in the 2 June 2002 issue of Science.
"NIH Trial to Test Chelation Therapy"
A News story by C. Holden in the 16 August 2002 issue of Science.
"Beefed-Up NIH Center Probes Conventional Therapies"
A News Focus by J. Couzin in the 18 December 1998 issue of Science.
BMC Complementary and Alternative Medicine
An open-access journal publishing original peer-reviewed research articles in complementary and alternative healthcare interventions; published by BioMed Central.
The Authors
Donald M. Marcus is in the Department of Medicine, Baylor College of Medicine, Houston.
Arthur P. Grollman is in the Department of Pharmacological Sciences at the State University of New York at Stony Brook.
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