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Executive Summary

FDA will need further studies to decide whether the widespread use of beta agonist bronchodilators can be linked to an increase in asthma-related deaths, FDA's Pulmonary-Allergy Drugs Advisory Committee concluded at its Dec. 12-13 meeting. Although the committee was presented with data from three studies that suggest that chronic use of inhaled beta agonists can adversely affect clinical outcome, the committee was unwilling to state that there is a causal relationship between chronic use of the drugs and a trend in increasing asthma mortality. The advisory committee called for more studies to clarify the issue. The concern over safety risks from the use of inhaled beta agonist bronchodilators came to a head with the publication of an 89-patient New Zealand study, conducted by Sears, et al. in the Dec. 8, 1990 issue of Lancet. In that study, only 30% of the 64 evaluable patients improved control of their asthma symptoms with regular administration of Boehringer Ingelheim's inhaled fenoterol whereas 70% of patients showed improved control when receiving a placebo and using a bronchodilator for symptom relief only. The year-long placebo-controlled crossover study found that asthma symptoms in the majority of patients deteriorated when regularly taking fenoterol. Commenting on the Sears study, committee member Leslie Hendeles, University of Florida, noted: "I'm fairly certain that what we're seeing in that data is more peculiar to that particular drug than a class effect, although I'm not really convinced that at a higher dose one couldn't reproduce that effect with other members of that pharmacologic group." In recommending that further studies be conducted to clarify potential adverse effects from inhaled beta agonists, the committee indicated that such studies should apply to drugs in development as well as those on the market. However, Hendeles said he could see "no reason to conduct additional studies" of marketed drugs. "I don't think that the currently available drugs are promoted for chronic prophylactic therapy [and] I don't believe the data convinces me that they are effective for that indication." He suggested that studies focus on the newer drugs, such as salmeterol (Glaxo's Serevent) and formoterol (Ciba-Geigy's Foradil), because these drug's clinical experience may justify prophylactic use. At a Dec. 11 meeting, Glaxo Holdings R&D Director Richard Sykes, PhD, said that in "two to three weeks" the company plans to file an NDA for use of its long-acting beta agonist Serevent for treatment of adult asthma (see story, p. 18). The committee considered five questions from FDA after hearing and discussing 13 hours of presentations on beta agonist bronchodilators during the course of the two-day meeting. Committee members spent about an hour-and-a-half addressing the questions, but did not vote. Committee members were generally in support of a study design proposed by committee member Harold Nelson, MD, National Jewish Center for Immunology and Respiratory Medicine, Denver. Nelson suggested a study design for beta agonists that would be one year in duration, involve a placebo control, assess acute versus chronic use, and include a two-week washout period for prior beta agonist use. He also suggested that studies look at more severe patients that are treated chronically with anti-inflammatories. FDA Pulmonary Drug Group Leader Eileen Leonard noted that traditional beta agonist studies involve 12 weeks of continuous therapy and usually use an active control. Committee members also said they would like beta agonist studies to look specifically at the potential adverse effects of bronchial hyperreactivity and myocardial toxicity in the elderly. Several committee members said they liked the idea of establishing a central registry to track the incidence of beta agonist-related adverse events. Committee Chairman Leonard Bernstein, MD, University of Cincinnati Medical Center, also recommended that some type of outcomes research be performed. The committee did not offer more detailed suggestions on how the studies should be conducted or who should sponsor them. In response to FDA's question of whether anti-inflammatories should be first-line therapy for asthma, either alone or concomitantly with inhaled beta agonists, Bernstein replied: "I think . . . that's a foregone conclusion and most people feel that way." He added that "obviously a combination would be required for most cases." State of the art medicine, as outlined in a recent National Heart, Lung & Blood Institute report ("The Pink Sheet" Feb. 11, p. 13), suggests that inhaled beta agonists be prescribed for treating mild asthma; inhaled or oral beta agonists plus an anti- inflammatory are suggested for moderate asthma; and beta agonists are used to treat severe asthma along with oral corticosteroids. The advisory committee's chief concern with inhaled beta-2 agonist bronchodilators is that they are apparently being overused by asthma patients in the U.S. Hendeles said that "overuse of inhaled beta agonists allows a patient to delay seeking medical care and institution of appropriate therapy, and that could lead to death." He said the danger from overuse of bronchodilators "is the most important thing that I've heard over the couple of days . . . and that in some way needs to be communicated to physicians, pharmacists and the lay public." To cut down on the overuse of inhaled beta agonists, Hendeles recommended that FDA "issue some kind of warning to pharmacists and physicians alike that the cannister ought to last a month, and if someone wants a refill . . . they need to talk to their physician." For example, he noted that pharmacists generally give patients two cannisters a week when providing albuterol refills. Hendeles also proposed that labeling for inhaled beta agonists be restricted only for acute use. Other committee members contended that restrictive labeling would needlessly limit physicians in their choice of treatments for asthma. Commenting on the Sears study results, Glaxo VP-Clinical Research James Palmer, MD, noted that "the numbers [of patients in the study groups] were small" and that "crossover designs can have problems with carry-over effect." He claimed that "the important thing is that the absolute changes that are seen between the treatment groups in this study are of doubtful clinical significance." In addition to the Sears study, the advisory committee also considered two epidemiological studies that supported a possible connection between beta agonist use and the recent rise in asthma mortality: a New Zealand case control study on asthma mortality associated with fenoterol use and an unpublished cohort study from the Saskatchewan Asthma Epidemiology Project. Epidemiological data from New Zealand during an "epidemic of asthma mortality" that occurred in the late 1970s and early 1980s were presented by Neil Pearce, PhD, Wellington School of Medicine, New Zealand. Three studies of this data "had the same results," said Pearce: "we found that patients who were prescribed fenoterol had twice the risk of death than those patients who were prescribed other beta agonists." He noted that the onset of the epidemic "coincided almost exactly" with the introduction of fenoterol to the New Zealand market in 1976. After the study results were published in the April 29, 1990 Lancet, Pearce reported, "fenoterol sales fell to some extent and . . . the [asthma] death rate fell from 2.2, the highest in the world, to 1.1." While the epidemiological data could "only be used to compare fenoterol with other beta agonists," Pearce suggested that "there may be a possible class effect of beta agonists . . . but more studies are needed for the others." Walter Spitzer, MD/PhD, McGill University, Montreal, presented data from the Saskatchewan Asthma Epidemiology Project's unpublished cohort study of 12,301 asthma sufferers in Saskatchewan from 1976-1986. During that period there were 44 deaths deemed to be "probably caused by asthma" and 85 near-death episodes. These cases were then matched to a total of 655 controls and the overall relative risk factor was determined for different treatments for chronic asthma. The study found that patients using fenoterol had a risk factor of 5.3, while patients using salbutamol had a risk factor of .9. The study also concluded that "for every additional cannister [of fenoterol] used per month, you double the risk of death or near-death," said Spitzer.

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