<< Back to Agenda

Slide 1: Clash Between Data, Practice, and Policy

Paul Shekelle, MD, Ph.D.

Slide 1: The Problem

• A health concern gets substantial public attention
• Pressure builds from all quarters to reach a policy decision
• High quality RCT data are not available to conclusively answer the question

What to do? The example of ephedra

Slide 2: Ephedra the Herb (3 pictures of herb)

Slide 3: Ephedrine the Molecule (Drawing of molecule)

Slide 5: Why Do People Use Ephedra?

• In China: used as part of a concoction for a variety of symptoms
• In Europe: approved in Germany to treat asthma and congestion
• In USA:
• To lose weight
• To improve athletic performance

Slide 6: References

"FDA targets herbal product" (Financial Times, London, 8/19/2002)

"Petition urges U.S. to ban supplements with ephedra" (NYT, 9/6/2001)

"Ephedra is now under intense scrutiny" (LA Times, 8/2/2002)

"For young athletes, limited gains--at a high risk (Washington Post, 4/9/02)

"Ephedrine: safe or lethal?" (USA Today, 11/8/2001)

Public Citizen asks Secretary of HHS to ban ephedra as a threat to public health

Ephedra is an "imminent hazard…" Senator Durbin

Slide 7

HHS Secretary Thompson announces that RAND will conduct comprehensive review of the existing science on ephedrine alkaloids (6/14/2002)

"The results of the RAND review will help FDA's scientists to develop future regulatory actions on dietary supplements containing ephedrine alkaloids."

Lester M. Crawford, DVM, PhD. Acting Commissioner, FDA (10/8/2002)

AHRQ, with funding from Office of Dietary Supplements and National Center for Complementary and Alternative Medicine, sponsor an Evidence Report by the Southern California Evidence Based Practice Center at RAND.

Slide 8: The Key Question (Scales)

• Greater Weight Loss
• Increased Athletic Performance
• Safety

Slide 9: Systematic Review & Meta-analysis of the Efficacy & Safety of Ephedra and Ephedrine Results of Weight Loss Comparisons (Flow Chart)

Slide 10: Results of Weight Loss Comparisions (Table)

Slide 11: Conclusions: Weight Loss

• Ephedra alone and in combination is associated with weight loss
• No long-term studies of effectiveness
• Few head-to-head comparisons with alternative therapies
• Ephedra likely to be less effective than weight loss drugs

Slide 12: Conclusions: Athletic Performance

• 8 studies identified
• None on Ephedra
• 6 by Bell and colleagues
• All studied particular interventions and outcomes, and could not be pooled statistically
• All studied small numbers of young, fit males and assessed immediate performance
• Studies report improved performance only for ephedrine + caffeine

Slide 13: Key Questions: Safety

• Does ephedra use have adverse effects?
• Does using ephedra increase the risk of heart disease or other serious and life-threatening events?

Slide 14: Adverse Events: Data from Controlled Clinical Trials (Table)

Slide 15: Adverse Events:Clinical Trials

• No deaths, heart attacks, or other serious adverse events reported in clinical trials
• Clinical trials studied only a few thousand people
• This number is too small to detect a rate of adverse events smaller than 1 per 1,000

Slide 16: Kile's Death Stuns Baseball (Picture of Los Angeles Newspaper Headline)

Slide 17: Exam Points to Kile's Heart ((Picture of Los Angeles Newspaper Headline)

Slide 18: Criteria for Classification of Case Reports as "Sentinel Events"

Sentinel Event

• Documentation of the adverse event
• Documentation that ephedra or ephedrine was consumed within the prior 24 hours (by report or toxicology examination)
• Documentation that other potential causes of the adverse event were evaluated and excluded

Possible Sentinel Event

• Documentation of the adverse event
• Documentation that ephedra or ephedrine was consumed within the prior 24 hours (by report or toxicology examination)
• Other potential causes exist or were not effectively excluded

Slide 19: FDA Reports of Adverse Events (Table)

Slide 20: EPHEDRA: Who's Telling the Truth (Headline from Time Magazine 8/26/02)

Slide 21: Conclusions of the Evidence Report (2/28/03)

• Neither side - the critics or the supporters - is completely right or wrong
• 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
• After use of a single dose
• Ephedra is associated with some side effects
• Upper GI symptoms, autonomic hyperactivity, psychiatric symptoms, palpitations

Slide 22: But does ephedra cause serious adverse events?

• Ephedrine acts on receptors in the cardiovascular system and in the brain
• Chemically related compounds have been proven to cause these same adverse events
• Phenylpropanolamine, amphetamines
• The sentinel events we identified are a signal that ephedra may also cause serious adverse events
• Recent case-control study reported an increased risk for hemorrhagic stroke with ephedra use
• Adjusted odds ratio of 3.95 (95% CI: 0.7-18.0; p=0.07)

Slide 23: Limitations of the Analysis

• 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 report adverse event data
• Under-reporting?
• 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
• In order to assess safety at the conventional threshold for statistical significance and inference, a definitive hypothesis-testing study is needed.

Slide 24: Key Issues to Consider

• There is no provable certainty; therefore, the question is what are the ramifications of a policy decision or non-decision, and how much uncertainty can we tolerate?
• In the case of ephedra, the degree of uncertainty regarding a causal relationship between use and serious adverse events did not meet the conventional "p<0.05" threshold.

Slide 25: Key Issues to Consider

• The time needed to conduct a hypothesis-testing study of ephedra would be 2-5 years.
• If ephedra is causally related to an increased risk of serious adverse events, then during the time period needed to conduct a study some number of ephedra users would succumb.
• If ephedra is not causally related to an increased risk of serious adverse events, then a decision to withdraw it from the market would deny some potential ephedra users the possibility of weight loss benefits we observed.

Slide 26: The Policy Decision

Policy decision was made to withdraw ephedra from the market.

Slide 27: Key Issues to Consider

<< Back to Agenda