R A Statistics Group How to Tell the President… Or At Least the Secretary of HHS …The Facts About Ephedra Sally C. Morton, RAND Statistics Group Southern California Evidence-Based Practice Center Southern California Evidence-Based Practice Center Shekelle PG, Hardy ML, Morton SC, Maglione M, Mojica WA, Suttorp MJ, Rhodes SL, Jungvig L, Gagné J. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance. A meta-analysis. JAMA. 2003;289(12)

R A Statistics Group Ephedra is an herbal dietary supplement regulated under the Dietary Supplement Health and Education Act of 1994 (DSHEA) Specifically forbids FDA to regulate Forbids disease treatment claims Places burden of proof for safety on the government Ephedra is sold as part of many “concoctions” Metabolife 356 Nature’s Nutrition – Formula 1 Ripped Fuel (Twin Labs), E’ola, Slacker II… Ephedra industry claims 3 billion “servings” are sold per year Ephedra Use in the United States

R A Statistics Group Systematic review project conducted at the AHRQ Southern California Evidence-Based Practice Center Conduct comprehensive literature search, including unpublished and non-English literature Conduct meta-analysis of clinical trial data as appropriate to assess efficacy of ephedra for weight loss and improved athletic performance Examine safety using data from clinical trials, published case reports, and FDA and Metabolife adverse event databases Ephedra: Clinical Efficacy and Side Effects Project

R A Statistics Group June 2002: Public Citizen asks HHS Secretary to ban ephedra as a threat to public health HHS Secretary Thompson announces that RAND will conduct a comprehensive review of the existing science on ephedrine alkaloids August 2002: Ephedra is an “imminent hazard…” Senator Durbin October 2002: “The results of the RAND review will help FDA's scientists to develop future regulatory actions on dietary supplements containing ephedrine alkaloids.” FDA Acting Commissioner Crawford Our Project Had Started in 2001…

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R A Statistics Group The Anecdotal Adverse Event Baltimore Orioles pitcher Steve Bechler dies on February 17, 2003 Ephedra is implicated "This was certainly a preventable death; it didn't have to occur, this kind of tragedy," said Broward County's chief medical examiner (CBS News 2/18/03).

R A Statistics Group Conclusions Of Our Evidence Report Released 2/28/03 Ephedra does promote short-term weight loss but long-term effects are unknown Ephedrine plus caffeine does have modest short-term effects on athletic performance Ephedra does cause some side effects such as palpitations and psychiatric symptoms (source: clinical trial data) The “sentinel” events (e.g., 5 deaths, 5 heart attacks, 11 strokes) we identified are a signal that ephedra may cause serious adverse events, and this effect is biologically plausible (source: adverse event case report files)

R A Statistics Group Clinical trials –Usual limitations for clinical trial meta-analysis –No deaths or other serious adverse events reported but insufficient sample size to detect a rate of adverse events smaller than 1 per 1000 Case reports: –Did not have access to all reports –Many reports did not contain sufficient documentation –No estimate of the number of people using ephedra –Study design considered insufficient to warrant conclusions regarding causality Definitive case-control study needed to assess safety Limitations of the Analysis

R A Statistics Group Federal Government Response (2/28/03) “HHS Acts to Reduce Potential Risks of Dietary Supplements Containing Ephedra,” FDA News Ban on advertising effects of ephedra on athletic performance Proposed new warning label for ephedra HHS Secretary Thompson says "We want to caution all Americans - particularly athletes and those who engage in strenuous activities - about using dietary supplements that contain ephedra. There continue to be serious questions about the risks surrounding this particular dietary supplement." Congressional Hearings 7/23-24/03: FDA Commissioner McClellan says “A ban on ephedra use is in the range of options we are considering."

R A Statistics Group Ephedra Education Council (3/12/03) The Rand report confirms that more than 55 clinical studies support the safety and benefits of the Ephedra/caffeine combination, when taken as directed by overweight, but otherwise healthy individuals. Recently announced efforts by the Food and Drug Administration (FDA) to regulate Ephedra should consider these studies in the agency's final rulemaking decision. Furthermore, FDA should also ban irresponsible marketing practices, a complete ban on use by minors, mandatory strict science-based serving recommendations and medical condition warnings for the labels of all Ephedra products. The Ephedra industry continues to call upon the Food and Drug Administration to adopt science-based regulations for Ephedra dietary supplement products. The industry is committed to working with FDA on appropriate measures that guarantee continued access for the millions of responsible adult Americans who consume these products every day for safe and effective weight loss."

R A Statistics Group How to Tell … The Facts Focus on a small number of conclusions and support with strong analyses –Promotes short-term weight loss, no long term studies, very limited evidence on athletic performance –Does cause some side effects –Sentinel events are a serious signal but further research needed to establish causality

R A Statistics Group How to Tell … The Facts Anticipate –Who will focus on which conclusions –The “spins” from different audiences and in multiple directions When you speak to journalists, politicians are listening Beware – yet accept – better yet use – the anecdote