NOTE: Guerry R. Thornton, Jr. is a partner in the Atlanta firm of Netlaw. He is a member of the Association of Trial Lawyers of American and has authored articles on mass tort litigation for Matthew Bender & Co., Trial Magazine and The National Law Journal. He is counsel in the Waters class action in Georgia and is handling individual product liability cases related to Fen/Phen and Redux.
COMMENT ON WYETH-AYERST REDUX STUDY
Wyeth-Ayerst announced a study related to Redux, or dexfenfluramine, on March 31, 1998, in a highly publicized conference at the Annual Meeting of the American College of Cardiology. It was advertised as the first randomized study of Redux and heart valve disease. The study was conducted by a panel at Georgetown University Medical Center and funded by Wyeth-Ayerst which licensed and marketed Redux.
The meeting was organized by the ACC and open to cardiologists and the media. I attended the meeting as a lawyer representing victims and as the author of a newsletter on the medical-legal issues concerning diet pills. Fortunately, I was the first lawyer to examine the Wyeth-Ayerst panel related to the safety and efficacy of Redux.
As the Wyeth study garnered world-wide headlines touting the safety of Redux, we have a public duty to demonstrate the flaws and limitations in this report. It is important to demonstrate Wyeth's systematic attempts to control public debate and its reliance upon biased safety data while failing to answer reliable evidence that Redux increases the risk of diseases that are more dangerous than valvular abnormalities.
The Wyeth study was promoted as a randomized, double-blinded, multi-center review involving 1,072 patients in three groups, those on Redux, sustained-release dexfenfluramine (which was never marketed) and a placebo. Based on my review of the initial data, the study is subject to challenge in these areas:
- it was restricted to short-term users (77 days median duration);
- it did not address primary pulmonary hypertension, a potentially fatal disease, and brain damage;
- it did find an increase in valve abnormalities in a higher percentage of Redux users than the placebo;
- it did not properly evaluate increases in valve leakage in users who were on Redux for longer periods, especially in view of the 12-month perscription guideline;
- it was funded by Wyeth and panel members serve as paid consultants to the company; and,
- it did not address efficacy issues, such as the absence of evidence that diet drugs effectively reduce mortality.
As a foundation for the study, Wyeth stated that its market research indicated that 76 percent of Redux users were on the drug for 60 days or less and 80 percent for 90 days or less. As to methodology, the study used the FDA's case definitions of valvular abnormalities and used groups that were demographically similar. Although the panel stated that they found no significant increase in the prevalence of "clinically relevant heart valve regurgitation after Redux usage", short term users did show an increase in mild or greater regurgitation. For instance, mild or greater aortic regurgitation occurred in 5.8 percent of dexfenfluramine and 3.6 percent of the placebo-treated patients.
Assuming conservative interpretations of echocardiograms, this is still a 60 percent increase in short-term users. Importantly, the study did not deal with the Fen-Phen combination, nor did it study patients on the drug for up to 12 months, the prescription period in the Redux insert. As reports indicate that aortic damage increases with the duration of use (See, Public Citizen State-ment of Dr. Lewis J. Rubin, September 23, 1997), Wyeth may have focused on short-term users to generate favorable publicity.
One glaring injustice in the manner in which the Wyeth study was reported is the fact that Dr. Heidi Connolly's research was ignored. As the Mayo Clinic cardiologist who published the original report in the August 1997 New England Journal of Medicine, Dr. Connolly spoke at the ACC Convention the same afternoon the Redux report was announced. She confirmed that data from her research continues to show "that up to 30 percent of patients who took diet drugs may develop valve disease." Dr. Connolly stated that patients who used diet pills increased the risk of valve disease by 15 times compared to the general population. She confirmed that the 30 percent rate corresponds well to Fen-Phen patients and those who took Redux alone or with phentermine. The median duration in her study was 9 months and a majority of the patients in the Mayo research had symptoms. Thus, Wyeth had comparable studies showing that the duration of use increased the incidence rate, yet it elected to restrict its test pool to short-term users.
The Wyeth report has sparked sharp criticism from one medical expert who is affiliated with Georgetown University. Dr. Michael Anchors, an internist who wrote the book Safer Than Fen-Phen by Prima Publications, notes that studies of Fen-Phen patients done while patients were on Fen-Phen showed 33-48 percent incidence of clinically relevant valve dysfunction. He claims Wyeth used patients who had been off Redux for 6 months because Wyeth believes that valve abnormalities may improve over time. Dr. Anchors has published a critique of the Redux study in which he concludes:
"The fact that the Redux group showed more abnormalities than the placebo group 6 months after the patients were withdrawn from a short course of Redux stiffens the assertion that Redux is associated with heart valve disease."
As evidence to support his conclusions, Dr. Anchors cites research that is being conducted jointly by Wyeth and the FDA in Cleveland which has developed an animal model for the disease. He knows of data which shows that animals on Redux or fenfluramine develop valve abnormalities similar to humans. This may be evidence that Wyeth-Ayerst has knowledge of scientific studies which may discredit the Redux study.
The most important omission in the study relates to the risk of developing PPH. When the Wyeth panel was questioned about this oversight, the experts touting the study maintained that the PPH risk is 18 per million users, repeating the defective warning that is the basis for liability claims. Reliable studies show a PPH incidence much higher than the warnings in the Redux insert. See, Abenhaim, et al., "Appetite-suppressants & the Risk of PPH", N. Eng. J. Med. 1996; 335:609-616. The international PPH study found a 20-fold increase in the risk of developing this deadly disease when the drugs were used six months or longer, knowledge that certain manufacturers may have had from anorexic drug research in Europe. Thus, Wyeth's experts can be challenged for mistating the PPH risk factors.
The Wyeth research does not demonstrate that the benefits of Redux outweighed its risks. In fact, the report seems to raise more questions than it answers. One result is clear: it presents weapons that will be used by both sides in suits that attack the safety and efficacy of appetite-suppressant medications.