|Fenoterol and Patient Deaths|
Excerpted from Blaming the Brain, by Elliot Valenstein. The Free Press, 1998. Pages 279-280 of the hardcover edition (from the section of footnotes to chapter 6).
Neil Pearce has recently described his experience following a study of the drug fenoterol, a beta adrenergic agonist used in inhalers by asthmatics. Epidemiologists in New Zealand started to notice an increase in cardiovascular-related deaths among asthmatics using bronchodilator aerosols containing fenoterol. The results of a more focused epidemiological study indicated a strong possibility that the use of inhaled fenoterol was responsible for the epidemic of asthma mortality. The authors of this study were not naive and they anticipated that their results might be challenged by the pharmaceutical company that markets fenoterol. Therefore, before submitting their manuscript for publication, they sent a report of the study and its conclusion to New Zealand's Department of Health, which then convened an independent review panel (The Asthma Task Force). The review panel called for some more data, which was supplied by Neil Pearce, and after the authors incorporated a few suggestions by the panel, a favorable report on the study was reached – with one member of the task force commenting that “these are the best data that will ever be available to try to answer this extremely important question.”
The fenoterol-asthma manuscript was then submitted to the British medical journal Lancet, which accepted it for publication after two external referees approved it with only minor changes in the text. In the meantime, the director-general of New Zealand's Health Department sent a copy of the manuscript to the Boehringer Ingelheim company, the manufacturer of fenoterol. The company immediately sent copies of the manuscript to reviewers it selected, requesting them to “identify important sources of bias” and “to evaluate the importance of each source of error.” Many of the responses of these reviewers seemed to have been evoked by the questions asked by the company, and the criticisms were generally unsubstantiated, contradictory, or of the nitpicking variety to which no clinical study is completely immune.
The Boehringer Ingelheim company then convened a “consensus meeting” to which it invited some of the reviewers it had initially hired. The “consensus meeting,” which was held in New York in April 1989, concluded that “the study design is seriously flawed and may lead to unjustified policy formulation and prescribing decisions.” The report that emerged from the “consensus meeting” was sent to the editors of Lancet, who wrote to the authors of the study:
Some of the commentaries have now been sent to us and they are causing some anxiety . Three possible courses of action face a journal having second thoughts about a paper accepted but not yet published... withdrawal ... counter convincingly the critical comments... publication in the second half of the journal accompanied by a highly critical editorial in the same issue.
The authors refused to back down, writing back that “we can counter convincingly the very critical comments,” and they expressed concern that an unconditional acceptance of a paper could be withdrawn “following submissions made by a pharmaceutical company.” To their credit, the editors of Lancet accepted the authors' response, and a publication date was set. Before publication, staff of New Zealand's Department of Health decided to send an abstract of the paper, accompanied by a cautionary letter, to all doctors in New Zealand. The Boehringer Ingelheim company got wind of this plan and wrote to the department conveying an implicit threat:
We are concerned at your intended communication with doctors.... Enclosing a copy of the abstract suggests Departmental approval... unless the Department's approach is modified we are left with no option but to take every steps available to us to protect ourselves.... We have learned that the content and ambiguity in your letter has caused substantial anxiety and confusion among asthma patients and doctors... the responsibility for the medical and legal consequences rests with you.... We expect [your next] letter to state that therapeutic conclusions cannot be drawn from the Crane et al. study.
The director-general of health then advised the department not to send out the abstract. After further intradepartmental discussion this decision was reversed and copies of the abstract were mailed, but the department's accompanying letter was softened. The asthma death rate in New Zealand dropped markedly after the publication of the study in Lancet. When several later studies confirmed the findings, there was overwhelming evidence that implicated fenoterol in the deaths of asthmatics. The drug was finally withdrawn. See: Pearce, N., “Adverse reactions: The fenoterol saga”, in Davis, P., ed., For Health or Profit? (New York: Oxford University Press, 1992), pp. 75-97.
© 2004 Alex Chernavsky email@example.com